Use and monitoring of inhaled nitric oxide with left ventricular assist devices

ABSTRACT

Described are systems and methods for administration of nitric oxide (NO) with use of left ventricular assists devices (LVADs), as well as systems and methods for monitoring the NO delivery devices and/or the LVAD.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application priority to U.S. Patent Application No. 62/294,711,filed on Feb. 12, 2016 and entitled “Use and Monitoring of InhaledNitric Oxide with Left Ventricular Assist Devices,” the contents ofwhich are incorporated herein by reference in their entirety.

TECHNICAL FIELD

Embodiments of the present invention generally relate to the field ofmethods and devices for delivering and monitoring inhaled nitric oxide(NO).

BACKGROUND

Modern semi-permanent continuous-flow left ventricular assist devices(LVADs) are cost-effective and durable surgically-implanted mechanicaldevices which augment or substitute for a poorly functioning ornonfunctioning diseased left ventricle of the heart to maintain bloodcirculation to the body. LVADs are now considered to be a reasonablealternative to orthotopic heart transplantation, especially given thesevere shortage of suitable donor organs. Continuous-flow LVADs havereplaced earlier pulsatile models because they are more durable, lesscumbersome, and have been shown to increase survival, exercise capacityand quality of life. LVADs are used to sustain patients with advancedcongestive heart failure (CHF) who cannot be managed medically either asa bridge-to-heart transplantation, as destination therapy or, in thosepatients whose CHF is deemed at least partially reversible, as abridge-to-recovery. The frequency of sufficient recovery to permit LVADexplantation is estimated to be 10-20% in CHF of non-ischemic etiologyand in <1% in ischemic CHF. LVAD implantation is generally indicated inCHF when cardiac index (CI) is <2 L/min/m², systemic systolic arterialpressure is <90 mm Hg, left atrial pressure is >20 mm Hg, or thesystemic vascular resistance is >1.57 mm Hg/mL. Advances in thedurability and miniaturization of LVADs, afforded by continuous-flowrather than pulsatile design, have enabled more extensive andlonger-duration utilization.

Unfortunately, failure of the right ventricle has been reported in 15%of continuous-flow LVAD recipients within the first 30 days followingimplantation and in 20-50% of LVAD recipients overall. As such, rightventricular failure remains a major limitation of LVAD utility, and isassociated with markedly poorer prognosis.

Furthermore, continuous-flow LVADs generate reduced pulsatility ofperipheral perfusion compared to pulsatile-flow LVAD devices and/or thenormal circulation derived from a well-functioning human heart asmeasured by pulsatility index, pulse pressure and/or the frequency ofopening of the aortic valve, and this reduced pulsatility has beenimplicated in a number of adverse events including reduced peripheralvascular compliance, gastrointestinal bleeding, arteriovenousmalformations, hemolysis, pump thrombosis, aortic insufficiency andlower rate of recovery of left ventricular function.

Accordingly, there is a need for adjunctive therapies that enhance theuse of LVADs and/or reduce the risk of right ventricular failureassociated with LVADs and/or reduce the risk of other LVAD-relatedadverse events.

SUMMARY

One or more aspects of the present invention provide new adjunctivetherapies that enhance the effectiveness of LVADs and/or reduce the riskof right ventricular failure associated with LVADs.

One aspect of the present invention relates to a method of determiningwhether a patient with pulmonary hypertension will resolve the pulmonaryhypertension with continued use of an LVAD. In various embodiments ofthis aspect, the method comprises measuring one or more pulmonaryhemodynamic parameters of a patient with an LVAD to obtain a firstpulmonary hemodynamic value; after obtaining the first pulmonaryhemodynamic value, administering inhaled NO to the patient with theLVAD; and measuring one or more pulmonary hemodynamic parameters of thepatient during or after the inhaled NO administration to obtain a secondpulmonary hemodynamic value. A significant change in the pulmonaryhemodynamic parameter from the first pulmonary hemodynamic value to thesecond pulmonary hemodynamic value can indicate that the patient islikely to resolve the pulmonary hypertension after continued use of theLVAD. For example, a significant change in the pulmonary hemodynamicparameter can be at least 10 mm Hg mPAP and/or at least 20% PVR, orequivalent changes as shown by echocardiography, MRI or other imagingtechnology.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 10 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, and about 60 minutes.

Exemplary pulmonary hemodynamic parameters include mean pulmonary arterypressure (mPAP), diastolic pulmonary artery pressure (dPAP), pulmonarycapillary wedge pressure (PCWP), transpulmonary gradient (TPG) andpulmonary vascular resistance (PVR). Other pulmonary hemodynamicparameters include combinations of and/or interrelations between theseparameters, such as the difference between dPAP and PCWP. The one ormore pulmonary hemodynamic parameters may be measured or estimated byany appropriate procedures, such as by performing a right heartcatheterization, MRI or echocardiography.

In one or more embodiments, the method further comprises placing thepatient on a heart transplant list if there is a significant change inthe pulmonary hemodynamic parameter from the first pulmonary hemodynamicvalue to the second pulmonary hemodynamic value, such as a decrease inmPAP of at least 10 mm Hg and/or a decrease in PVR at least 20%. In someembodiments, the method further comprises explanting the LVAD andimplanting a donor heart in the patient.

As an alternate to the above thresholds of 10 mm Hg mPAP and/or 20% PVR,other significant changes in the pulmonary hemodynamic parameter may bea decrease of 5 mm Hg (for pressure-related parameters such as mPAP orTPG) or a change in the parameter of at least 5% (for all parameters).Exemplary significant changes in the pulmonary hemodynamic parameterinclude a change of at least 5 mm Hg, at least 6 mm Hg, at least 7 mmHg, at least 8 mm Hg, at least 9 mm Hg, at least 10 mm Hg, at least 15mm Hg, at least 20 mm Hg, or at least 25 mm Hg, and/or at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40% or at least 50%.

Another aspect of the present invention relates to a method ofoptimizing the settings of an LVAD. In various embodiments of thisaspect, the method comprises administering inhaled NO to a patienthaving an LVAD; performing an echocardiogram on the patient during theadministration of inhaled NO; and adjusting or setting one or moreparameters of the LVAD during the echocardiogram and during theadministration of inhaled NO. Instead of performing an echocardiogram,other appropriate techniques may be used to set the LVAD parameters. Inone or more embodiments, adjusting or setting the LVAD parameters duringadministration of NO helps to optimize cardiac output.

In one or more embodiments of this aspect, adjusting or setting one ormore parameters of the LVAD comprises one or more of (i) determining alow pump speed setting for the LVAD based on the minimal pump speednecessary for the patient's aortic valve to open with each heart beat or(ii) determining a high speed setting for the LVAD based on the pumpspeed at which the septum of the patient's heart flattens. In someembodiments, augmenting aortic valve opening and closing withoutflattening the septum could include setting a constant speed, or settinga range over which the speed could be modulated to accomplish this, suchas in pulse modulation continuous flow.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 10 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, about 60 minutes, about 1.5 hours, about 2hours, about 2.5 hours and about 3 hours.

In some embodiments, the LVAD settings are changed over a series ofincremental adjustments. For example, the LVAD pump speed may beadjusted upwards in two or more steps. One or more or all of these stepsmay be performed during the administration of inhaled NO as describedherein.

Another aspect of the present invention relates to a method of reducingthe risk of right ventricular failure during LVAD use. In variousembodiments of this aspect, the method comprises administering inhaledNO to a patient with an LVAD for at least 12 hours a day for at least 20days.

Due to the fact that a patient with an LVAD had preexisting leftventricular dysfunction, it may be important to ensure that the LVAD isproperly functioning prior to administering inhaled NO. Accordingly, insome embodiments, the method further comprises confirming that the LVADis functioning properly before administering inhaled NO.

In one or more embodiments, the inhaled NO is administered after apatient has been weaned from cardiopulmonary bypass (CPB).

The inhaled NO may be administered for several days to many months oreven longer. Exemplary treatment times include 10 days, 15 days, 20days, 25 days, 30 days, 35 days, 40 days, 45 days, 2 months, 3 months, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 1 year, 1.5 years, or 2 years. In some embodiments, the patientis administered inhaled NO indefinitely.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 12 hours a day. Exemplaryinhaled NO concentrations include about 5 ppm, about 10 ppm, about 15ppm, about 20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40ppm, about 45 ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65ppm, about 70 ppm, and about 80 ppm. Exemplary NO administration timesinclude about 12 hours a day, about 14 hours a day, about 16 hours aday, about 18 hours a day, about 20 hours a day, about 22 hours a day,or up to 24 hours a day.

Alternatively, the dose of NO may be prescribed based on the patient'sideal body weight (IBW). Exemplary NO doses may be in the range of about25 to about 150 μg/kg IBW/hr, such as about 25, about 30, about 35,about 40, about 45, about 50, about 60, about 70, about 80, about 90,about 100, about 110, about 120, about 130, about 140 or about 150 μg/kgIBW/hr.

In one or more embodiments, the method further comprises monitoring oneor more output parameters of the LVAD and/or one or more hemodynamicparameters of the patient, comparing the one or more output parametersand/or the one or more hemodynamic parameters to a predetermined range,and adjusting the dose of inhaled NO if the one or more outputsparameters and/or the one or more hemodynamic parameters are outside ofthe predetermined range. In some embodiments, the method furthercomprises providing an alert if the one or more output parameters and/orthe one or more hemodynamic parameters are outside of the predeterminedrange. Such alerts can include an audible alert, a visual alert, asomatosensory alert (e.g. vibration) and/or a text alert. The inhaled NOdose may be adjusted automatically (e.g. by the NO delivery device or acontrol system in communication with the NO delivery device), or may bemanually adjusted by a physician or other user.

Examples of LVAD parameters that may be monitored include, but are notlimited to, pump speed (e.g. rpm), pump flow (e.g. L/min), pulsatilityindex, battery level, and LVAD status (e.g. operational, presence orabsence of warnings).

Another aspect of the present invention relates to a method ofmonitoring the left ventricle of a patient with an LVAD to determinewhether the left ventricle of the patient is improving. In variousembodiments of this aspect, the method comprises reducing the pump speedof the LVAD or turning off the LVAD; measuring one or more pulmonaryhemodynamic parameters of the patient to obtain a first pulmonaryhemodynamic value; preloading the left ventricle by administeringinhaled NO to the patient; and measuring one or more pulmonaryhemodynamic parameters after or during administration of inhaled NO toobtain a second pulmonary hemodynamic value. In some embodiments, thepulmonary hemodynamic parameter is selected from LAP, PCWP and CO, ormay be any assessment of the left ventricular reserve to compensate forincreased left ventricular preload that can be measured through rightheart catheterization, echocardiographic, MRI or other techniques.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 10 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, about 60 minutes, about 1.5 hours, about 2hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours or about 8 hours.

According to one or more embodiments, an increase in LAP and/or PCWPfrom the first pulmonary hemodynamic value to the second pulmonaryhemodynamic value of less than 5 mm Hg indicates that the left ventricleis improving. Other exemplary values that indicate an improvement in theleft ventricle include an LAP and/or PCWP increase of less than 1 mm Hg,2 mm Hg, 3 mm Hg, 4 mm Hg, 6 mm Hg, 7 mm Hg, 8 mm Hg, 9 mm Hg, 10 mm Hg,11 mm Hg, 12 mm Hg, 13 mm Hg, 14 mm Hg or 15 mm Hg. In some embodiments,the method further comprises modifying treatment if the left ventricleis improving, such as explanting the LVAD from the patient. Othermodifications in treatment can include changing the supportivemedication (e.g. diuretics and/or inotropic medications) that thepatient is given, such as reducing the supportive medication.

Yet another aspect of the present invention relates to a method ofexercising a heart of a patient having an LVAD. In various embodimentsof this aspect, the method comprises reducing and/or modulating the pumpspeed of the LVAD or turning off the LVAD; preloading the left ventricleby administering inhaled NO to the patient for at least 5 minutes;discontinuing the inhaled NO administration; and repeating thepreloading and discontinuation to exercise the left ventricle of thepatient's heart.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 5 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about 5minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 1.5hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours,about 4 hours, about 5 hours, about 6 hours, about 7 hours or about 8hours.

Alternatively, the dose of NO may be prescribed based on the patient'sideal body weight (IBW). Exemplary NO doses may be in the range of about25 to about 150 μg/kg IBW/hr, such as about 25, about 30, about 35,about 40, about 45, about 50, about 60, about 70, about 80, about 90,about 100, about 110, about 120, about 130, about 140 or about 150 μg/kgIBW/hr.

The preloading of the left ventricle may be performed multiple times perday, such as twice a day, three times a day, four times a day, fivetimes a day, six times a day, seven times a day, eight times a day, ninetimes a day or ten times a day. Alternatively, the preloading may beperformed once a day. If the preloading is performed multiple times perday, the preloading procedures may be clustered together (e.g. spacedapart by several minutes or a couple hours) or may be spread outthroughout the day. The preloading of the left ventricle may also beperformed once a week, two days a week, three days a week, four days aweek, five days a week, six days a week, or seven days a week. Inexemplary embodiments, the left ventricle is preloaded several times aday for several days a week, such as two to five times a day for two tofour days a week or other combinations of the above daily and weeklypreloading schedules.

Yet another aspect of the present invention relates to a method ofreducing the risk of adverse events during LVAD use. In variousembodiments of this aspect, the adverse events are associated withreduced pulsatility caused by LVAD use and/or associated with impairedNO-mediated vascular function.

In various embodiments of this aspect, the method comprisesadministering inhaled NO to a patient with a continuous-flow orsemi-pulsatile LVAD for at least 12 hours a day for at least 20 days.

Due to the fact that a patient with an LVAD had preexisting leftventricular dysfunction, it may be important to ensure that the LVAD isproperly functioning prior to administering inhaled NO. Accordingly, insome embodiments, the method further comprises confirming that the LVADis functioning properly before administering inhaled NO.

In one or more embodiments, the inhaled NO is administered after apatient has been weaned from cardiopulmonary bypass (CPB).

The inhaled NO may be administered for several days to many months oreven longer. Exemplary treatment times include 10 days, 15 days, 20days, 25 days, 30 days, 35 days, 40 days, 45 days, 2 months, 3 months, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 1 year, 1.5 years, or 2 years. In some embodiments, the patientis administered inhaled NO indefinitely.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 12 hours a day. Exemplaryinhaled NO concentrations include about 5 ppm, about 10 ppm, about 15ppm, about 20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40ppm, about 45 ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65ppm, about 70 ppm, and about 80 ppm. Exemplary NO administration timesinclude about 12 hours a day, about 14 hours a day, about 16 hours aday, about 18 hours a day, about 20 hours a day, about 22 hours a day,or up to 24 hours a day.

Alternatively, the dose of NO may be prescribed based on the patient'sideal body weight (IBW). Exemplary NO doses may be in the range of about25 to about 150 μg/kg IBW/hr, such as about 25, about 30, about 35,about 40, about 45, about 50, about 60, about 70, about 80, about 90,about 100, about 110, about 120, about 130, about 140 or about 150 μg/kgIBW/hr.

In one or more embodiments, the method further comprises monitoring oneor more output parameters of the LVAD and/or one or more hemodynamicparameters of the patient, comparing the one or more output parametersand/or the one or more hemodynamic parameters to a predetermined range,and adjusting the dose of inhaled NO if the one or more outputsparameters and/or the one or more hemodynamic parameters are outside ofthe predetermined range. In some embodiments, the method furthercomprises providing an alert if the one or more output parameters and/orthe one or more hemodynamic parameters are outside of the predeterminedrange. Such alerts can include an audible alert, a visual alert, asomatosensory alert (e.g. vibration) and/or a text alert. The inhaled NOdose may be adjusted automatically (e.g. by the NO delivery device or acontrol system in communication with the NO delivery device), or may bemanually adjusted by a physician or other user.

Examples of LVAD parameters that may be monitored include, but are notlimited to, pump speed (e.g. rpm), pump flow (e.g. L/min), pulsatilityindex, battery level, and LVAD status (e.g. operational, presence orabsence of warnings).

Yet another aspect relates to a method of optimizing the inhaled NO doseto be used in conjunction with an LVAD, such as a continuous-flow orsemi-pulsatile LVAD. In various embodiments of this aspect, the methodcomprises measuring endothelial function of a patient having acontinuous-flow or semi-pulsatile LVAD, administering inhaled NO to thepatient at a first dose, measuring the endothelial function of thepatient during the administration of inhaled NO, and adjusting theinhaled NO dose to optimize endothelial function. Any appropriatetechniques may be used to measure the endothelial function, including,but not limited to, flow-mediated dilation (FMD) and/or reactivehyperemic index (RHI). In one or more embodiments, adjusting the NO dosehelps to optimize the endothelial function and reduce the risk ofadverse events associated with impaired NO-mediated vascular function.

In some embodiments, the method further comprises measuring one orNO-related molecules and/or other biomarkers of endothelial function inthe patient's blood and/or plasma. Exemplary NO-related moleculesinclude whole blood and erythrocyte nitrite (NO₂ ⁻), nitrate (NO₃ ⁻)heme-nitrosylated hemoglobin [Hb(FeII)NO] and cysteine nitrosylatedhemoglobin (also known as S-nitrosohemoglobin SNO-Hb), and nitrosylatedplasma proteins. Other biomarkers of endothelial function include, butare not limited to, pulse amplitude tonometry (measuring post ischemicswelling of the fingertip) and peripheral arterial tonometry (usingultrasound to measure the size of the brachial artery after a bloodpressure cuff is released).

Yet another aspect of the present invention relates to a system forcoordinating operation of the LVAD and the NO delivery device. Such asystem may be used in any of the indications or methods describedherein. In various embodiments of this aspect, the system comprises acontrol system in communication with the NO delivery device and/or theLVAD, wherein the control system monitors one or more parameters of theNO delivery device and/or one or more parameters of the LVAD andprovides an alert if one or more parameters of the NO delivery deviceand/or LVAD are outside of a predetermined range. The system may alsocomprise the NO delivery device and/or the LVAD itself.

In one or more embodiments, the control system reduces a pump speed ofthe LVAD if there is a failure of the NO delivery device. The controlsystem may also initiate a weaning procedure for the NO delivery deviceif there is a failure of the LVAD.

The control system may be integral to the NO delivery device, integralto the LVAD or a component of a stand-alone control module.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above recited features of the presentinvention can be understood in detail, a more particular description ofthe invention, briefly summarized above, may be had by reference toembodiments, some of which are illustrated in the appended drawings. Itis to be noted, however, that the appended drawings illustrate onlytypical embodiments of this invention and are therefore not to beconsidered limiting of its scope, for the invention may admit to otherequally effective embodiments.

FIG. 1 illustrates an exemplary NO delivery device that can be used inaccordance with one or more embodiments of the invention

FIG. 2 illustrates an exemplary NO delivery device that can be used inaccordance with one or more embodiments of the invention;

FIG. 3 illustrates an exemplary NO delivery device in communication withan LVAD that can be used in accordance with one or more embodiments ofthe invention;

FIG. 4 illustrates an exemplary hardware configuration that can be usedin accordance with one or more embodiments of the invention;

FIG. 5 illustrates exemplary input and output parameters that can beused in accordance with one or more embodiments of the invention;

FIG. 6 illustrates an exemplary main menu with mode selection that canbe used in accordance with one or more embodiments of the invention;

FIG. 7 illustrates an exemplary main menu with alarm settings that canbe used in accordance with one or more embodiments of the invention;

FIG. 8 illustrates an exemplary main menu with configuration settingsthat can be used in accordance with one or more embodiments of theinvention;

FIG. 9 illustrates an exemplary submenu for assessment of the likelihoodof pulmonary hypertension resolution that can be used in accordance withone or more embodiments of the invention;

FIG. 10 illustrates an exemplary submenu for optimization of LVADsettings that can be used in accordance with one or more embodiments ofthe invention;

FIG. 11 illustrates an exemplary submenu for reducing the risk of rightventricular failure that can be used in accordance with one or moreembodiments of the invention;

FIG. 12 illustrates an exemplary submenu for assessment of leftventricular function that can be used in accordance with one or moreembodiments of the invention;

FIG. 13 illustrates an exemplary submenu for heart exercise that can beused in accordance with one or more embodiments of the invention; and

FIG. 14 illustrates an exemplary submenu for clinician setting of thecontrol system that can be used in accordance with one or moreembodiments of the invention.

DETAILED DESCRIPTION

Nitric Oxide for Inhalation

INOmax® (nitric oxide) for inhalation is an approved drug product. TheFDA-approved prescribing information for INOmax® dated 2013 is attachedas Appendix 1, and so forms part of the present disclosure, and also isincorporated by reference herein in its entirety. INOmax® is a selectivepulmonary vasodilator, which, in conjunction with ventilatory support orother appropriate agents, is indicated for the treatment of tem′ andnear-term (>34 weeks gestation) neonates with hypoxic respiratoryfailure associated with clinical or echocardiographic evidence ofpulmonary hypertension, where it improves oxygenation and reduces theneed for extracorporeal membrane oxygenation. The recommended dose ofINOmax® for the approved indication is 20 ppm, maintained for up to 14days or until the underlying oxygen desaturation has resolved. Weaningshould occur gradually. Adverse reactions per the label includemethemoglobinemia and nitrogen dioxide levels, both which can be dosedependent.

Inhaled NO may be administered via a NO delivery device such as theINOmax DSIR®, INOmax® DS or INOvent® delivery devices, each of whichdelivers operator-determined concentrations of NO in conjunction with aventilator or breathing gas administration system after dilution withoxygen or an oxygen/air mixture. Other NO delivery devices and featuresof NO delivery devices are described below, including NO deliverydevices having novel features not present in currently available NOdelivery devices.

The source of NO used in any of the presently disclosed methods anddevices can be a cylinder of compressed gas containing NO, typically asa mixture with an inert gas such as nitrogen or helium. TheNO-containing gas can be generated by manufacturing the gasesseparately, mixing them in an appropriate ratio, and introducing theminto an appropriate cylinder under pressure. The mixing can occur in twosteps: first diluting bulk NO with nitrogen to a concentration of, e.g.,5,000 ppm or 28,600 ppm in interim cylinders, and then diluting thatmixture further by introducing the mixture into the final cylinders andfilling them with more nitrogen to produce a concentration of, e.g., 100ppm or 800 ppm in the final cylinders. Care is taken not to introduceany water or oxygen into the cylinders. The cylinders can be equippedwith an appropriate valve, shipped to the point of use, and attached toa NO delivery device to facilitate inhalation of the gas by the patient.

The source of NO can instead be a NO-generating device that generates NOfrom a suitable nitrogen source, such as air (see for reference U.S.Pat. No. 5,396,882, incorporated herein by reference) or nitrogendioxide (see for reference U.S. Pat. No. 7,560,076, incorporated hereinby reference). The source of nitrogen dioxide can be, for example, acanister of compressed nitrogen dioxide gas or a container of N₂O₄(which, when treated under appropriate conditions, will give offnitrogen dioxide). Manufacturing a source of nitrogen dioxide caninclude the steps of compressing nitrogen dioxide gas into a suitablecontainer or introducing N₂O₄ in liquid form into a suitable container.The container can be supplied in a device that includes a filtercontaining a reducing agent or antioxidant, such as ascorbic acid, whichreduces the nitrogen dioxide to form NO at the patient's bedside. At thepoint of administration, such a NO-generating device is typicallyattached to a gas-delivery device (such as a ventilator) to facilitateinhalation of the newly formed NO gas by the patient.

Definitions

As used herein, the term “pulmonary hemodynamic parameter” refers to anyparameter used to describe or evaluate the blood flow through the heartand pulmonary vasculature. Examples of pulmonary hemodynamic parametersinclude, but are not limited to, mean pulmonary artery pressure (mPAP),diastolic pulmonary artery pressure (dPAP) [also known as pulmonaryartery diastolic pressure (PADP)], systolic pulmonary artery pressure(sPAP) [also known as pulmonary artery systolic pressure (PASP)],pulmonary capillary wedge pressure (PCWP) [also known as pulmonaryartery wedge pressure (PAWP)], left atrial pressure (LAP),transpulmonary gradient (TPG), pulmonary vascular resistance (PVR) andcardiac output (CO).

Many of the pulmonary hemodynamic parameters described above areinterrelated. For example, PCWP is often used as a more convenient, lessinvasive approximation of LAP. As another example, PVR is related tomPAP, PCWP and CO according to the following equation:PVR∝(mPAP−PCWP)/CO

As yet another example, TPG is the difference between mPAP and PCWP asshown by the following equation:TPG=mPAP−PCWP

As a further example, mPAP is related to dPAP and sPAP according to thefollowing equation:mPAP=(⅔)dPAP+(⅓)sPAPIn some embodiments, the pulmonary hemodynamic parameters are measureddirectly, such as during a right heart catheterization. In otherembodiments, the pulmonary hemodynamic parameters are estimated and/orevaluated through other techniques such as magnetic resonance imaging(MRI) or echocardiography.

The phrase “resolution of pulmonary hypertension (PH)” or variationsthereof refers to a decrease in PH below a clinically relevantthreshold. One example of resolution of PH is when the mPAP of a patientdecreases below a threshold of 25 mmHg. However, in patients with severeright ventricular failure, the ventricle can be so weak that it cannotgenerate sufficient force to raise sPAP so that the mPAP is at least 25mmHg In such patients, PH and resolution thereof may be evaluated byanalyzing the difference between dPAP and PCWP.

Right Ventricular Failure in LVAD Implanted Patients

As described above, right ventricular failure is a common problem afterLVAD implantation. Post-LVAD right-sided heart failure is primarilyrelated to the dynamic effects of the LVAD itself and/or the underlyingright ventricular disease, as post-operative right heart failure occursin only a small proportion of orthotopic heart transplants whenperformed in a similar population.

Post-LVAD right ventricular failure may be defined pathophysiologicallyas inability of the right ventricle to maintain adequate loading of theLVAD-assisted left ventricle despite adequate right ventricle preload,or to do so only at the expense of significantly elevated central venouspressure. Post-LVAD right heart failure is generally definedoperationally as the need for implantation of a right ventricular assistdevice (RVAD), or the need for reinstitution of inhaled NO for greaterthan 48 hours, or the need for inotropic pharmacological therapy forgreater than 14 days. Recent retrospective studies have each implicatedvarious different pre-implantation clinical and hemodynamic parametersas being predictive of post-LVAD right heart failure with littleconsensus as to the most informative or most predictive factors; thusfull understanding and accurate prediction of post-implantation rightheart failure remains clinically problematic and mechanisticallycontroversial. Putative predictive factors have ranged from non-specificdemographic, clinical and laboratory measures of overall disease burdenor patient “frailty”, to conventional hemodynamic and echocardiographicmeasures of left ventricle, right ventricle and pulmonary vascularstatus, to very specific and specialized functional imaging parametersof the right ventricle. The pathophysiology of right ventricular failureafter LVAD implantation appears to be multi-factorial, and includespre-operative right ventricular dysfunction and pulmonary hypertension(PH), right ventricular ischemia, peri-operative fluctuations inpulmonary vascular resistance (PVR) in the setting of cardiopulmonarybypass (CPB), excessive right ventricular preload, and alteredinterventricular balance, although the relative importance of each ofthese factors is strongly debated. Superimposed perioperative proceduresand/or complications thereof, such as intra-operative mechanical and/orischemic damage to the right ventricle, and intra-operative hemorrhagerequiring extensive fluid, colloid or blood product resuscitation, havealso been invoked as acute predisposing or exacerbating factors forperi-operative right heart failure associated with LVAD implantation.Importantly, the direct and indirect effects of the LVAD itself on theanatomy and function of the left ventricle are also implicated ascausing or contributing to post-implantation right ventriculardysfunction and right heart failure, despite optimization of LVADadjustments and pharmacological support.

Interactions Between the Left and Right Ventricles in Congestive HeartFailure

In the healthy heart, the left ventricle is estimated to contribute 80%of the contractile flow and up to two-thirds of the contractile pressuregenerated by the right ventricle through a process termed mechanicalsystolic ventricular interaction (SVI). The (patho)physiologicalinteractions between the left ventricle and the right ventricle in CHFare quite complex. The right ventricle may be directly damaged by theunderlying disease process affecting the left ventricle in CHF. Mostcommonly, right ventricular failure in CHF results from increased rightventricular afterload due to chronic pulmonary vascular congestion andPH consequent to the primary left ventricular dysfunction. Additionally,dilation of the left ventricle in CHF realigns the anatomy ofinterventricular septal musculature to a less efficient transverseorientation, further impairing SVI and therefore overall rightventricular contractility. When combined with the increased rightventricle afterload, dysfunctional SVI unleashes a vicious cycle ofprogressive right ventricular dysfunction and right ventricular failureReciprocally, as the failing right ventricle dilates, it intrudes andinterferes with the relaxation (diastolic) filling of the left ventricle(termed diastolic ventricular interaction [DVI]), further exacerbatingpulmonary vascular congestion and PH, creating a superimposed additionalvicious cycle of progressive left ventricular failure and rightventricular failure. An additional form of remote interventricularinteraction occurs at the level of the peripheral circulation, whereinthe increased central systemic blood volume and central venous pressurein CHF increases right ventricular preload and right ventricular fillingfurther increasing interventricular septal intrusion into the leftventricle and thereby further worsening DVI. Lastly, a further level ofinterventricular interaction occurs at the level of the pulmonarycirculation, where chronic elevation of pulmonary venous and capillarypressures causes pulmonary vascular remodeling which, over time createsa relatively fixed, structurally-mediated increase in PVR, furtherworsening PH and right ventricular afterload (defined as World HealthOrganization [WHO] Group 2 Pulmonary Hypertension Secondary toLeft-Sided Heart Disease).

World Health Organization Group 2 PH Secondary to Left-Sided HeartDisease

Up to three quarters of patients with end-stage CHF exhibit some degreeof PH and right ventricular dysfunction, and one-third to one-half havemoderate to severe or “fixed” PH unresponsive to vasodilator or inotrophchallenge. Pharmacologic challenge has generally included somecombination of inotropes (dobutamine, dopamine, milnirone), nonspecificvasodilators (nitroglycerin, sodium nitroprusside [SNP]) and/orpartially or completely selective pulmonary vasodilators (prostacyclin,prostacyclin analogues, prostaglandin E1, sildenafil, inhaled NO)administered pre- or post-LVAD implantation or orthotopic hearttransplant. The chronically failing left ventricle increases left atrialand pulmonary venous pressure which increases pulmonary artery pressure(PAP) and right ventricular afterload. With chronic stress, thepulmonary vasculature remodels, resulting in an increased PVR thatfurther increases PAP out of proportion to the increased pulmonaryvenous pressure leading to an increase in trans-pulmonary pressuregradient (TPG) in approximately one-third or more of advanced CHFpatients. However, the extent to which this increased PVR and TPG ismediated by tonic (and hence acutely reversible) compensatory pulmonaryvasoconstriction versus relatively fixed structural vascular remodeling,and the degree to which each of these components is ultimatelyreversible in advanced CHF is often difficult to predict based onpreviously known methods. As the key intermediary between rightventricular output and left ventricular preload, the dynamic status ofthe pulmonary vasculature in patients with chronic CHF before, duringand after LVAD placement is both highly complex and critically importantto clinical outcome. PH unresponsive to pharmacological therapy has beenassociated with an increased risk of right heart failure and overallpoor prognosis following orthotopic heart transplant, and is consideredto be a contraindication for that procedure. In contrast, the predictivepower of preoperative hemodynamic attributes of PH for the developmentof post-LVAD right heart failure is complex. Indeed, both lowpre-implantation PAP (perhaps indicative of poor right ventricularcontractility) and high pre-implantation PVR have been reported to bepredictive of the subsequent development of post-LVAD right heartfailure. The presence of fixed PH in end-stage CHF is now considered tobe an indication for LVAD therapy versus a contraindication for hearttransplant, based in part on the consistent observation that chronicunloading of the left ventricle by a well-functioning LVAD over timereverses “fixed” Group 2 PH in CHF patients in whom PH had beenotherwise unresponsive to pharmacological intervention before LVADimplantation, thus rendering these patient eligible for hearttransplant. Maximum improvement in PH status appears to be reachedwithin the first 6 months of LVAD support, and remain stable thereafter.Thus, although the LVAD-treated end-stage CHF population will likelybecome preferentially enriched in patients with WHO Group 2 PH targetingbridge-to-transplant, destination therapy or even bridge-to-recovery,the importance of avoiding LVAD-related adverse events, which areassociated with poorer post-heart transplant prognosis, has recentlybeen emphasized.

Interventricular Interactions and Right Heart Failure after LVADImplantation

Although the beneficial effects of continuous-flow LVADs on survival andquality-of-life as well as WHO Group 2 PH have been well documented, thedirect and indirect effects of these devices on right ventricularfunction have only recently been evaluated in detail. The same SVI andDVI operative in non-LVAD-supported CHF may also play a clinically andtherapeutically important role in post-LVAD right heart failure. Theimplanted LVAD actively increases left ventricular outflow whichdecompresses the left ventricle, thereby decreasing pulmonary vascularcongestion and reducing right ventricular afterload; however the sameaugmented LVAD outflow increases right ventricular preload which mayoverwhelm the functional capacity of the previously stressed and/ordamaged right ventricle. The decompression of the left ventricle alsoresets SVI and DVI. Current post-operative hemodynamic LVAD managementprimarily targets restoration of normal systemic peripheral end-organ(e.g. renal and hepatic) perfusion (as measured by CI) in order topenult gradual weaning of inotropic agents and diuretics. Fluid therapyis generally targeted to maintain initial pump speed >2 liters/min witha right atrial filling pressure <20 mm Hg). After hospital discharge,attributes of pulmonary vascular congestion and PH and the need forinotropic pharmacological support generally decline as measures ofperipheral end-organ perfusion progressively improve gradually over aperiod of days to weeks. Despite initial reductions in pulmonaryvascular congestion, PH and excessive right ventricular afterload (whichtogether should improve right ventricular function), right ventriculardysfunction as assessed by transthoracic echocardiogram may remainimpaired for up to 3 months following successful LVAD implantation(although more rapid improvement has been reported in stable LVADpatients not requiring inotropic support). The still-weakened rightventricle may be unable to accommodate the increased forward flowgenerated by the LVAD-assisted left ventricular output, posing acontinuing risk of right heart failure. The associated elevation ofright arterial pressure one month post-LVAD implantation is linked withimpaired exercise tolerance as reliably assessed by the distance walkedin six minutes (6 MWD) and is predictive of increased mortality risk.Persistent post-LVAD right ventricular dysfunction may reflectdiminished intrinsic ability of the right ventricle to undergoself-repair and/or the fact that therapeutic hemodynamic adjustmentsprioritize the systemic circulation leaving the still-weakened rightventricle exposed to non-optimized hemodynamic stresses.

Post-Operative Management and Adjustment of LVADs

Both the intrinsic right ventricle and the implanted LVAD arepreload-dependent and afterload-sensitive, and adequate but notexcessive preload of the right ventricle is important to maintainadequate left ventricle/LVAD filling without excessive right ventricularvolume overload in the immediate post-operative period. LVAD flows mustbe kept low enough to avoid right ventricular volume overload but highenough to sustain adequate end-organ perfusion. Inotropes, e.g.milrinone, dobutamine and epinephrine, used to wean from CPB are oftencontinued for days after implantation. Nitroglycerin, SNP, nesiritideand sildenafil have been used to lower Inhaled NO and prostacyclin havealso been used to reduce PVR in order to do so without compromisingsystemic perfusion. Nevertheless, depending upon the setting of thecontinuous-flow LVAD rotational speed, right ventricular outflow throughthe pulmonary circulation may be inadequate to reliably fill the leftventricle, resulting in the development of negative pressure in the leftventricle. This negative left ventricular pressure not only compromisesLVAD function, but also draws the interventricular septum leftward,disrupting SVI and essentially eliminating any septal contribution toright heart contractility, further reducing right ventricular outflow.This occurrence can precipitate severe right ventricular dysfunction andovert clinical right ventricular failure, which may decrease LVADpreload further impairing its function thereby causing worsening heartfailure. In the intra-operative setting during LVAD implantation,trans-esophageal echocardiography (TEE) continuously monitors theposition of the interventricular septum during LVAD adjustment andweaning from CPB; this is particularly important to monitor and managethe acute effects of CPB-withdrawal on the dynamic status of thepulmonary vasculature, which can produce severe acute intra-operative orperi-operative PH. Sub-acute post-operative right ventricular failuresecondary to interventricular septal deviation and dysfunction issuspected when trans-thoracic echocardiography (TTE) reveals a dilatedright ventricle accompanied by a small left ventricle and an aorticvalve which remains closed due to negative left ventricular pressure.During the post-operative hospitalization, averaging 6 ICU and 20 totalinpatient days, periodic TTE assessment of interventricular septaldeviation predicts right ventricular failure and guides LVAD rotationalspeed adjustment to minimize leftward interventricular septal deviationand the consequent risk of right ventricular dysfunction and rightventricular failure. For example, a “ramped speed study” under TTEmonitoring may be used to adjust the optimal pump speed taking intoaccount changes in ventricular dimensions, displacement of theinteratrial and interventricular septa, and the frequency of aorticvalve opening as well as evidence of inadequate left ventricularpreloading and right ventricular dysfunction. This TTE-directedoptimization may be especially important in patients with poor 6 MWD.Reduction of LVAD speed to optimize right ventricular function and/ormanage post-LVAD right ventricular failure may require temporaryreintroduction of inotropic pharmacological support and/or intravenousvasodilators to maintain adequate systemic end-organ perfusion. Despitethese intensive measures, right ventricular failure remains a leadingcause of early mortality after implantation of even the most moderncontinuous-flow LVADs. Furthermore, current approaches to optimize LVAD,right arterial and right ventricular hemodynamics with inotropic supportand/or conventional intravenous vasodilators is limited by the fact thatthese agents may induce arrhythmias and/or systemic hypotension,increase oxygen demand, and worsen oxygenation due to pulmonaryventilation-perfusion mismatching, leaving ample room for new approachesthat would optimize LVAD function and reduce the risk of rightventricular failure while avoiding these serious pharmacologic sideeffects. Furthermore, other therapeutic approaches may be needed toenable right ventricular outflow through the pulmonary circulation tomaintain sufficient left ventricular preload to adequately fill theLVAD-assisted left ventricle at LVAD settings sufficient to maintainadequate end-organ perfusion during the critical post-implantationperiod.

Pulmonary Vasodilators in the Management of Patients with LeftVentricular Assist Devices

Acute pulmonary vasoreactivity testing (AVT) by right heartcatheterization with selective pulmonary vasodilators such as inhaled NOis routinely performed in other forms of PH such as pulmonary arterialhypertension (PAH, or WHO Group 1 Pulmonary Hypertension). AVT withinhaled NO is only rarely and cautiously performed in non-LVAD-supportedpatients with CHF prior to heart transplantation, because acutehighly-selective reduction in PVR and right ventricular afterload mayoverload the failing left ventricle thereby increasing right arterialand pulmonary venous pressure, potentially precipitating acute pulmonaryedema. Instead, “fixed” versus “reversible” PH in advanced CHF isusually interrogated by the hemodynamic response or lack thereof tocombinations of systemically-administered non-pulmonary-specificvasodilators such as SNP, nitroglycerin or adenosine and inotropicagents administered acutely, or in some studies, for over 72 hours. Attimes, acute or longer infusion of highest tolerated doses (i.e. free ofsystemic hypotension or other systemic side effects) of prostacyclin andprostaglandin E₁ in conjunction with inotropes or non-specificvasodilators have been used for PH-reversibility in this setting.Inhaled or intravenous prostanoids may be currently consideredpreferable to inhaled NO in non-LVAD-supported CHF patients in some butnot all geographies despite significant decreases in systemic vascularresistance (SVR) and the clear demonstration that chronic intravenousprostacyclin therapy increases mortality in patients with end-stage CHF.

Because early extubation, removal of monitoring lines and ambulation arerecommended, TTE becomes a primary tool to aid in the regulation of LVADsettings and hemodynamic fluid and pharmacological therapy in thepost-acute post-implant setting. Management is complicated by the factthat right ventricular and both the pulmonary and systemic circulationsare simultaneously undergoing complex dynamic interactions andadaptations to the newly functioning LVAD and the fact that mostvasoactive drugs affect both circulatory systems simultaneously, e.g.SNP dilates both systemic and pulmonary resistance vessels. The highpulmonary selectivity and very short half-life of inhaled NO are idealattributes to classify, manage and optimize the pulmonary vascularstatus in CHF patients on LVAD support, and to optimize LVAD performancein this setting. In the post-operative period, once the acute effects ofCPB-induced PH have abated and the patient stabilized on a hemodynamicregimen, AVT with inhaled NO under echocardiographic and/or right heartcatheterization guidance could be used to determine if inhaled NO shouldbe continued in order to adjust left ventricular preload to optimize SVIand LVAD performance and reduce the risk of perioperative andpostoperative acute right ventricular dysfunction and right ventricularfailure. Specifically, doses of inhaled NO would be titrated against theright ventricular performance including measures of SVI and LVADrotational speed, power and flow, until the correct combination isachieved to normalize/optimize right ventricular function, SVI, cardiacoutput, pulsatility and other hemodynamic parameters. In those patientsin who CI or LVAD or right ventricular performance appears to benefit,inhaled NO would be continued during the taper of inotrope and/orintravenous systemic vasodilators. These parameters would then bere-monitored with echocardiographic assessment to maintain optimalsettings during the post-acute recovery period. It would be anticipatedthat the provision of critical right ventricular afterload reduction andleft ventricular preload enhancement during this period would permitincreased CI with less LVAD power, improve pulse index, improveperipheral perfusion and exercise tolerance, and hasten and improveearly cardiac rehabilitation, as well as reduce the risk of right heartfailure. Additionally, the post-acute response to inhaled NO could behighly predictive of the likelihood of subsequent maximum resolution ofresidual PH over 6-months resulting from chronic CHF, particularly inthose patients whose PH may have been characterized preoperatively as“fixed” by lack of response to the combination of inotropic agents andsystemic vasodilators, as the effectiveness of these agents is oftentolerability-limited. Thus, inhaled NO could represent a new paradigm inthe optimal management of patients with functioning LVADs over the days,weeks and months following implantation.

New Indications Relating to the Use of Inhaled NO with LVADs

In view of the above, aspects of the present invention provide for theutilization of inhaled NO as adjunctive therapy post-LVAD implantation.The inhaled NO therapy may be commenced pre-operatively pre-implantationor intra-operatively before, during or directly after implantation; suchinhaled NO therapy may be continued beyond the time period in which itis clinically required in order successfully counteract the acute andtemporary PH that occurs as a direct consequence of the CPB procedureitself. Alternatively, inhaled NO could be instituted (or re-instituted)after successful weaning from CPB and the direct consequence thereof.

In various aspects of the present invention, inhaled NO would thusly beutilized for one or more novel applications to predict and prevent thedevelopment of right ventricular failure post successful weaning fromCPB in LVAD recipients. As discussed above, right ventricular failureafter institution of LVAD support may be consequent to the developmentor persistence of PH, further impairment of right ventricularcontractility secondary to alterations in SVI and DVI or otherventricular interactions between the RV and the “unloaded” leftventricle, or further intrinsic impairment of right ventricularcontractility given the known susceptibility of the right ventricle tomyocardial preservation injury during CPB. Differentiation among thesecontributing causes is important since they would be manageddifferently.

One aspect of the present invention provides a method to predict whichpost-implantation LVAD patients with PH are likely to resolve their PHwith continued LV unloading by a functional LVAD. Those patientsexhibiting a significant acute reduction in TPG and/or mPAP and/or PVRand/or other measures such as the difference between dPAP and PCWP withinhaled NO would be those more likely to resolve their increased TPGand/or mPAP and/or PVR following LVAD treatment, e.g. after severalmonths of LVAD treatment.

When acute vasoreactivity testing (AVT) is performed pre-LVADimplantation, the PAP is a combination of increased pulmonary vascularresistance and elevated post-capillary pressure measured as either PCWPor right arterial pressure (RAP). The PCWP and RAP effect would beremoved once the LVAD is in place, making the AVT results more clearlyrelated to pulmonary vascular resistance, not confounded by increasedPCWP and RAP. Accordingly, this aspect of the present invention providesan enhanced predictive tool by performing the AVT after LVADimplantation.

In various embodiments of this aspect, the method comprises measuringone or more pulmonary hemodynamic parameters of a patient with an LVADto obtain a first pulmonary hemodynamic value; after obtaining the firstpulmonary hemodynamic value, administering inhaled NO to the patientwith the LVAD; and measuring one or more pulmonary hemodynamicparameters of the patient during or after the inhaled NO administrationto obtain a second pulmonary hemodynamic value. A significantimprovement in the pulmonary hemodynamic parameter from the firstpulmonary hemodynamic value to the second pulmonary hemodynamic value,for example a decrease of at least 10 mm Hg and/or at least 20% canindicate that the patient is likely to resolve the pulmonaryhypertension after continued use of the LVAD.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 10 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, and about 60 minutes

Exemplary pulmonary hemodynamic parameters include mean pulmonary arterypressure (mPAP), transpulmonary gradient (TPG) and pulmonary vascularresistance (PVR). The one or more pulmonary hemodynamic parameters maybe measured by any appropriate procedures, such as by performing a rightheart catheterization.

Other known methods of performing acute vasoreactivity testing (AVT)with inhaled NO may also be used in addition to or as an alternative tothe methods described above with respect to this aspect of theinvention, provided that such AVT is performed after LVAD implantation.

In one or more embodiments of this aspect, the method further comprisesplacing the patient on a heart transplant list if the decrease in thepulmonary hemodynamic parameter from the first pulmonary hemodynamicvalue to the second pulmonary hemodynamic value is at least 10 mm Hgand/or at least 20%. In some embodiments, the method further comprisesexplanting the LVAD and implanting a donor heart in the patient.

As an alternate to the above thresholds of 10 mm Hg and/or 20%, othersignificant decreases in the pulmonary hemodynamic parameter may be atleast 5 mm Hg, at least 6 mm Hg, at least 7 mm Hg, at least 8 mm Hg, atleast 9 mm Hg, at least 15 mm Hg, at least 20 mm Hg, or at least 25 mmHg, and/or at least 5%, at least 10%, at least 15%, at least 25%, atleast 30%, at least 35%, at least 40% or at least 50%.

Another aspect of the present invention provides a method to useadministration of inhaled NO during the adjustment and setting of theLVAD parameters and hemodynamic pharmacotherapy and fluid replacementtherapy once the acute effects of prior CPB on pulmonary hemodynamicshave elapsed.

One current methodology of setting an LVAD involves setting therevolutions/min (rpm) rate of an LVAD (such as a HeartMate II LVAD (HMII)) to provide adequate cardiac output and achieve optimal leftventricular decompression, while maintaining a pulsatility index(defined as the maximum LVAD flow rate minus the minimum LVAD flow ratedivided by the average LVAD flow rate) of 3.5 to 4. Although modern“continuous-flow” LVAD devices do not themselves have valves that openand close to generate pulsatile flow, the flow rate through thesedevices at any device setting varies depending upon the pressuregradient between the left ventricle and the aorta such that theincreased systolic pressure with each contraction of the left ventricletransiently increases flow through the LVAD creating some pulsatilevariation in blood flow. In addition, the fixed-rate speed of acontinuous-flow LVAD is usually adjusted to maximize left ventriculardecompression and to improve cardiac output, while simultaneouslyallowing for a minimum aortic valve opening ratio of 1:3 (i.e. the leftventricular systolic pressure achieves a sufficiently high pressurerelative to aortic pressure to permit opening of the aortic valve onceout of every three systoles despite the continuing efflux of bloodthrough the LVAD).

Another current methodology of setting an LVAD involves optimizing therpm speed, both hemodynamically and echocardiographically, at the timeof LVAD placement, before the patient is discharged from the hospital(i.e., after admission for LVAD placement) and if clinical events suchas new symptoms or suction events warranted further adjustment. However,these hemodynamic and echocardiographic assessments used to adjust LVADsettings are static in that they are performed at the left ventricularpreload exhibited by the patient at the time and condition under whichthe test is performed (usually at rest).

The use of inhaled NO during part of the test procedure to maximallyrelax the pulmonary vessels and lower PVR would provide information onthe maximal left ventricular preload that the right ventricle is able togenerate unfettered by acutely-reversible pulmonary vasoconstriction.Such dynamic (rather than static) assessment would provide additionalinformation to optimize any particular group of settings of the LVAD toproduce the desired cardiac out and pulsatility parameters whileavoiding the generation of left ventricular suction as determined bysimultaneous TTE. The novel use of inhaled NO as an adjunct to adjustingLVAD parameters should improve the efficiency and safety of functioningLVADs, which should result in improved cardiac output, pulsatilityindices and exercise tolerance, and reduce the risk of right heartfailure.

As the above prior methods simply understand the extent to which LVADand right ventricular settings and read-outs reflect the current levelof PH without dissecting PH into fixed versus reversible by dynamictesting, these methods limit the range of options within which LVADfunction would have to operate efficiently during the recovery periodpost-LVAD implantation. Accordingly, the more effective and accurateadjustment in LVAD parameters provided by this aspect of the inventioncan result in improved LVAD efficiency, cardiac output, end-organperfusion, and exercise tolerance, and retesting with this paradigm andperiodically re-setting LVAD parameters can hasten full recovery.

Accordingly, this aspect of the present invention relates to a method ofoptimizing the settings of an LVAD by utilizing inhaled NO. In variousembodiments of this aspect, the method comprises administering inhaledNO to a patient having an LVAD; performing an echocardiogram or similarfunctional hemodynamic or cardiac imaging assessment on the patientduring the administration of inhaled NO; and adjusting or setting one ormore parameters of the LVAD during the echocardiogram and during theadministration of inhaled NO. In one or more embodiments, adjusting orsetting the LVAD parameters during administration of NO helps tooptimize cardiac output, end-organ perfusion, LVAD efficiency and/orexercise tolerance.

In one or more embodiments of this aspect, adjusting or setting one ormore parameters of the LVAD comprises one or more of (i) determining alow pump speed setting for the LVAD based on the minimal pump speednecessary for the patient's aortic valve to open with each heart beat or(ii) determining a high speed setting for the LVAD based for example onthe pump speed at which the septum of the patient's heart flattens.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 10 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, about 60 minutes, about 1.5 hours, about 2hours, about 2.5 hours and about 3 hours.

In some embodiments, the LVAD settings are changed over a series ofincremental adjustments. For example, the LVAD pump speed may beadjusted upwards in two or more steps. One or more or all of these stepsmay be performed during the administration of inhaled NO as describedherein.

Another aspect of the present invention provides for long-term use ofinhaled NO after LVAD implantation. In one or more embodiments of thisaspect, if AVT favorably predicts that PH will resolve after continueduse of the LVAD, and/or if the settings and read-out and/or the TTEindicate more efficacious LVAD function and hemodynamic status underinhaled NO challenge, then the treating physician may wish to continueadministering inhaled NO to the patient continuously for all or part ofthe convalescent period. In various embodiments, inhaled NO would beadministered to the patient during all or part of the day over a periodof days, weeks or months to maintain the favorable LVAD function and/orhemodynamic status. Periodic testing may be performed as described aboveboth on and off inhaled NO for a short period of time, such that whensufficient recovery had occurred so that inhaled NO was no longerproducing and hemodynamic or TTE change, the patient may be carefullyweaned from inhaled NO. This treatment would be expected to result inimproved cardiac output and exercise tolerance more quickly, and reducethe risk of right heart failure.

In various embodiments of this aspect, the method comprisesadministering inhaled NO to a patient with an LVAD for at least 12 hoursa day for at least 10 days. The inhaled NO may be administered forseveral days to many months or even longer. Exemplary treatment timesinclude 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days,45 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years.In some embodiments, the patient is administered inhaled NOindefinitely.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 12 hours a day. Exemplaryinhaled NO concentrations include about 5 ppm, about 10 ppm, about 15ppm, about 20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40ppm, about 45 ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65ppm, about 70 ppm, and about 80 ppm. Exemplary NO administration timesinclude about 12 hours a day, about 14 hours a day, about 16 hours aday, about 18 hours a day, about 20 hours a day, about 22 hours a day,or up to 24 hours a day.

Due to the fact that a patient with an LVAD had preexisting leftventricular dysfunction, it may be important to ensure that the LVAD isproperly functioning prior to administering inhaled NO. Accordingly, insome embodiments, the method further comprises confirming that the LVADis functioning properly before administering inhaled NO.

In one or more embodiments, the inhaled NO is administered after apatient has been weaned from cardiopulmonary bypass (CPB).

As an alternative to a constant concentration of NO, the dose of NO maybe prescribed based on the patient's ideal body weight (IBW). ExemplaryNO doses may be in the range of about 25 to about 150 μg/kg IBW/hr, suchas about 25, about 30, about 35, about 40, about 45, about 50, about 60,about 70, about 80, about 90, about 100, about 110, about 120, about130, about 140 or about 150 μg/kg IBW/hr.

In one or more embodiments, the method further comprises monitoring oneor more output parameters of the LVAD and/or one or more hemodynamicparameters of the patient, comparing the one or more output parametersand/or the one or more hemodynamic parameters to a predetermined range,and adjusting the dose of inhaled NO if the one or more outputsparameters and/or the one or more hemodynamic parameters are outside ofthe predetermined range. In some embodiments, the method furthercomprises providing an alert if the one or more output parameters and/orthe one or more hemodynamic parameters are outside of the predeterminedrange. The inhaled NO dose may be adjusted automatically (e.g. by the NOdelivery device or a control system in communication with the NOdelivery device), or may be manually adjusted by a physician or otheruser, such as in response to an alert.

Examples of LVAD parameters that may be monitored include, but are notlimited to, pump speed (e.g. rpm), pump flow (e.g. L/min), pump power,pulsatility index, battery level, and LVAD status (e.g. operational,presence or absence of warnings).

In some embodiments, the LVAD has a minimum and/or maximum pump speedthat is set by the physician, and can be specific for the individualpatient. Alternatively or additionally, the LVAD may also have a minimumand/or maximum pump speed set by the manufacturer of the LVAD.Regardless of whether the minimum and/or maximum pump speed is set by aphysician or the manufacturer, exemplary minimum pump speeds include 100rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 6000 rpm, 700 rpm, 800 rpm, 900rpm, 1,000 rpm, 1,500 rpm, 2,000 rpm, 2,500 rpm, 3,000 rpm, 4,000 rpm,5,000 rpm, 6,000 rpm, 7,000 rpm, 8,000 rpm, 9,000 rpm, 10,000 rpm,11,000 rpm, 12,000 rpm, 13,000 rpm, 14,000 rpm and 15,000 rpm, andexemplary maximum pump speeds include 1,000 rpm, 1,500 rpm, 2,000 rpm,2,500 rpm, 3,000 rpm, 4,000 rpm, 5,000 rpm, 6,000 rpm, 7,000 rpm, 8,000rpm, 9,000 rpm, 10,000 rpm, 11,000 rpm, 12,000 rpm, 13,000 rpm, 14,000rpm, 15,000 rpm, 20,000 rpm and 30,000 rpm. The minimum and maximum pumpspeeds may depend on the design of the LVAD.

Similarly, in some embodiments, the LVAD has a minimum and/or maximumpump flow that is set by the physician, and can be specific for theindividual patient. Alternatively or additionally, the LVAD may alsohave a minimum and/or maximum pump flow set by the manufacturer of theLVAD. Regardless of whether the minimum and/or maximum pump flow is setby a physician or the manufacturer, exemplary minimum pump speedsinclude 1 L/min, 1.5 L/min, 2 L/min, 2.5 L/min, 3 L/min, 3.5 L/min, 4L/min, 4.5 L/min, 5 L/min, 6 L/min, 7 L/min, 8 L/min, 9 L/min and 10L/min, and exemplary maximum pump flows include 3 L/min, 3.5 L/min, 4L/min, 4.5 L/min, 5 L/min, 6 L/min, 7 L/min, 8 L/min, 9 L/min, 10 L/min,11 L/min, 12 L/min, 13 L/min, 14 L/min and 15 L/min. The minimum andmaximum pump flows may depend on the design of the LVAD.

In some embodiments, the pulsatility index of the LVAD has a minimumand/or maximum threshold. As explained above, the pulsatility index isthe maximum pump flow minus the minimum pump flow, divided by theaverage pump flow. As the pulsatility index is an indication of how muchsupport the LVAD is providing to the heart (a higher pulsatility indexindicates that the LVAD is providing more support), high pulsatilityindices can be a cause of concern. Accordingly, exemplary maximumpulsatility indices include values of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 20.

In some embodiments, the battery level of the LVAD is monitored. As alow battery can indicate a future or imminent shutdown of the LVAD, whenthe battery level of the LVAD drops below a certain threshold, theinhaled NO dose may be lowered, a weaning protocol may be initiated,and/or an alert is provided. Examples of minimum battery levels include30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% batteryremaining or 6 hours, 5 hours, 4 hours, 3 hours. 2 hours, 1 hour, 30minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3minutes, 2 minutes or 1 minute of battery life remaining.

Similarly, other indicators of LVAD malfunction or complete LVAD failuremay be monitored, and the inhaled NO dose may be adjusted, a weaningprotocol may be initiated and/or an alert may be provided. Again, theinhaled NO dose may be adjusted automatically (e.g. by the NO deliverydevice or a control system in communication with the NO deliverydevice), or may be manually adjusted by a physician or other user.

Another aspect of the present invention relates to a method ofmonitoring the left ventricle of a patient with an LVAD. In variousembodiments of this aspect, the method comprises reducing the pump speedof the LVAD or turning off the LVAD; measuring one or more pulmonaryhemodynamic parameters of the patient to obtain a first pulmonaryhemodynamic value; preloading the left ventricle by administeringinhaled NO to the patient; and measuring one or more pulmonaryhemodynamic parameters of the patient after or during administration ofinhaled NO to obtain a second pulmonary hemodynamic value. In someembodiments, the pulmonary hemodynamic parameter is selected from LAP,PCWP and CO, or may be any assessment of the left ventricular reserve tocompensate for increased left ventricular preload that can be measuredthrough right heart catheterization, echocardiographic, MRI or othertechniques.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 10 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about50 minutes, about 55 minutes, about 60 minutes, about 1.5 hours, about 2hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours or about 8 hours.

According to one or more embodiments, an increase in LAP and/or PCWPfrom the first pulmonary hemodynamic value to the second pulmonaryhemodynamic value of less than 5 mm Hg indicates that the left ventricleis improving. Other exemplary values that indicate an improvement in theleft ventricle include an LAP and/or PCWP increase of less than 1 mm Hg,2 mm Hg, 3 mm Hg, 4 mm Hg, 6 mm Hg, 7 mm Hg, 8 mm Hg, 9 mm Hg, 10 mm Hg,11 mm Hg, 12 mm Hg, 13 mm Hg, 14 mm Hg or 15 mmHg. In some embodiments,the method further comprises modifying treatment if the left ventricleis improving, such as explanting the LVAD from the patient. Othermodifications in treatment can include changing the supportivemedication (e.g. diuretics and/or inotropic medications) that thepatient is given, such as reducing the supportive medication.

Another aspect of the present invention relates to a method ofexercising a heart of a patient having an LVAD. In various embodimentsof this aspect, the method comprises reducing and/or modulating the pumpspeed of the LVAD or turning off the LVAD; preloading the left ventricleby administering inhaled NO to the patient for at least 5 minutes;discontinuing the inhaled NO administration; and repeating thepreloading and discontinuation to exercise the left ventricle of thepatient's heart.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 5 minutes. Exemplary inhaledNO concentrations include about 5 ppm, about 10 ppm, about 15 ppm, about20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm. Exemplary NO administration times include about 5minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 1.5hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours,about 4 hours, about 5 hours, about 6 hours, about 7 hours or about 8hours.

The preloading of the left ventricle may be performed multiple times perday, such as twice a day, three times a day, four times a day, fivetimes a day, six times a day, seven times a day, eight times a day, ninetimes a day or ten times a day. Alternatively, the preloading may beperformed once a day. If the preloading is performed multiple times perday, the preloading procedures may be clustered together (e.g. spacedapart by several minutes or a couple hours) or may be spread outthroughout the day. The preloading of the left ventricle may also beperformed once a week, two days a week, three days a week, four days aweek, five days a week, six days a week, or seven days a week. Inexemplary embodiments, the left ventricle is preloaded several times aday for several days a week, such as two to five times a day for two tofour days a week or other combinations of the above daily and weeklypreloading schedules.

In some embodiments, the first instance or first few instances of theexercising of the patient's left ventricle is performed under the directsupervision of a physician, but once an appropriate exercise protocolhas been determined for a patient, then the exercise protocol may beperformed under patient control or may be automated by the NO deliverydevice and/or control system.

Another aspect of the present invention relates to a method of reducingthe risk of adverse events during LVAD use. In particular, it isbelieved that inhaled NO can improve cardiovascular function of LVADrecipients with functioning LVADs, reduce the risk of adverse eventsassociated with continuous-flow or semi-pulsatile LVADs (e.g.thrombosis, gastrointestinal bleeding) and improve the function oftransplanted hearts by making the cardiovascular system more compliant.

A specific deficiency in continuous-flow LVADs is that the reducedpulsatility of peripheral perfusion generated by these devices comparedto pulsatile-flow LVAD devices and/or the normal circulation derivedfrom a well-functioning human heart as measured by pulsatility index,pulse pressure and/or the frequency of opening of the aortic valve hasbeen implicated in a number of adverse events including reducedperipheral vascular compliance, gastrointestinal bleeding, arteriovenousmalformations, hemolysis, pump thrombosis, aortic insufficiency andlower rate of recovery of left ventricular function. These adverseevents can also be associated with semi-pulsatile LVADs.

Evidence of deranged microvascular function following continuous-flowLVAD support has been documented by several sensitive techniquesevaluating post-ischemic autoregulation of blood flow, includingflow-mediated dilation (FMD) of the brachial artery and the reactivehyperemic index (RHI), both of which has been shown to be predominantlymediated by locally released NO.

While not wishing to be bound by any particular theory, it is believedthat diminished LVAD-generated pulsatility is linked to derangement ofNO-mediated vascular autoregulatory function because pulsatile flow isconsidered the key generator of microvascular directional shear stressat the level of the microvascular endothelial cell that is stronglyimplicated in the autoregulation of NO biology in the vascular system.Thus, it is believed that at least some of the adverse events associatedwith continuous-flow LVAD's and their reduced pulsatility could besecondary to impaired NO-mediated autoregulatory vascular function.

Shear stress, and hence pulsatility, is a key factor in adapting organperfusion to changes in cardiac output presumably in part throughregulation of NO. Deranged NO-mediated autoregulatory vascular functionis reflected not only in peripheral vessels but also in coronary vesselsas well, including an association with a higher rate of in-stentthrombosis following percutaneous coronary intervention. It is believedthat impaired NO-mediated coronary vascular autoregulation could providea potential mechanism that would contribute to reduced LV recoveryduring continuous-LVAD support. NO not only mediates autoregulation ofvascular tone, but also modulates platelet activation and adhesion, suchthat deranged NO regulation could contribute to the increased thrombosisassociated with continuous-flow LVAD support. Attributes of NO-mediatedvascular dysfunction are considered to be significant overall riskfactors for adverse cardiovascular outcomes in the general population.Indeed, some authors have suggested that impaired endothelial dilationis the ultimate cause of cardiovascular diseases such as coronary arterydisease and peripheral artery disease. These widespread effects of NO onvascular health are thought to be mediated in large part by modulatingoxidative stress through the control of nitrosylation of a wide range ofregulatory proteins.

Inhalational NO could therefore improve endothelial function andvascular health, and thereby important clinical outcomes, in patients onlong-term continuous-flow LVAD support, through two related andpotentially complementary or synergistic mechanisms. Firstly, asdiscussed above, inhaled NO, by dilating pulmonary vessels, wouldincrease left ventricular preload and improve left ventricular filling,thereby increasing the frequency of aortic valve opening and closing,and hence pulsatility for any given LVAD speed setting. This effectmight be more dominant during periods of rest or sleep, or duringperiods of increased cardiac output demand such as exercise, dependingupon the characteristics of the LVAD device and setting.

Secondly, inhaled NO also has the potential to improve NO-mediatedvascular autoregulatory function and health independent of its effect ofcirculatory pulsatility, by improving NO bioavailability throughout theperipheral and coronary circulation. NO can be generated by NO synthase(NOS) or by the breakdown of nitrite or other compounds to NO.Inhalation of NO for even short periods of time (e.g. two hours)increases the circulating levels of a variety of molecules that have thepotential to regenerate NO within the microcirculation including nitrite(NO₂ ⁻), nitrate (NO₃ ⁻) and S-nitrosohemoglobin. These and otherNO-derive molecules have been invoked in the beneficial so-called“distal effects” of inhaled NO. For example, inorganic nitrite is anendogenous substance produced by the oxidation of NO. under aerobicconditions (such as in the lung) but conversely, in acidic conditionssuch as might be found in ischemic tissues, NO₂ ⁻ can be chemically andenzymatically reduced back to NO. where it has favorable effectsalleviating some of the consequences of local ischemia including theamelioration of ischemia-reperfusion injury. Thus, inhaled NO isexpected to improve and/or sustain the tissue integrity andautoregulation of the peripheral vasculature and the tissues which itsupplies, including the myocardium, through a complex cascade ofNO-mediated biochemical effects in the setting of endothelialdysfunction that accompanies prolonged continuous-flow LVAD support.

Accordingly, embodiments of the present invention provide for theadministration by inhalation of NO at doses and for durations that areexpected to (1) improve pulsatility through the NO's direct hemodynamicaction on the pulmonary vasculature thereby promoting left ventricularfilling, aortic valve opening and closure, and thereby maximizepulsatile flow and/or (2) increase peripheral NO bioavailability throughprovision NO precursors in the form of NO metabolites such as NO₂ ⁻, NO₃⁻, nitrosohemoglobin and other that are formed in the lung as a resultof NO inhalation and transported by the circulation to peripheraltissues where NO can be reformed further reducing endothelialdysfunction.

In various embodiments of this aspect, the method comprisesadministering inhaled NO to a patient with an LVAD for at least 12 hoursa day for at least 10 days. The inhaled NO may be administered forseveral days to many months or even longer. Exemplary treatment timesinclude 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days,45 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years.In some embodiments, the patient is administered inhaled NOindefinitely.

In some embodiments of this aspect, the inhaled NO is administered at aconcentration of 5 to 80 ppm for at least 12 hours a day. Exemplaryinhaled NO concentrations include about 5 ppm, about 10 ppm, about 15ppm, about 20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40ppm, about 45 ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65ppm, about 70 ppm, and about 80 ppm. Exemplary NO administration timesinclude about 12 hours a day, about 14 hours a day, about 16 hours aday, about 18 hours a day, about 20 hours a day, about 22 hours a day,or up to 24 hours a day.

Due to the fact that a patient with an LVAD had preexisting leftventricular dysfunction, it may be important to ensure that the LVAD isproperly functioning prior to administering inhaled NO. Accordingly, insome embodiments, the method further comprises confirming that the LVADis functioning properly before administering inhaled NO.

In one or more embodiments, the inhaled NO is administered after apatient has been weaned from cardiopulmonary bypass (CPB).

As an alternative to a constant concentration of NO, the dose of NO maybe prescribed based on the patient's ideal body weight (IBW). ExemplaryNO doses may be in the range of about 25 to about 150 μg/kg IBW/hr, suchas about 25, about 30, about 35, about 40, about 45, about 50, about 60,about 70, about 80, about 90, about 100, about 110, about 120, about130, about 140 or about 150 μg/kg IBW/hr.

In one or more embodiments, the method further comprises monitoring oneor more output parameters of the LVAD and/or one or more hemodynamicparameters of the patient, comparing the one or more output parametersand/or the one or more hemodynamic parameters to a predetermined range,and adjusting the dose of inhaled NO if the one or more outputsparameters and/or the one or more hemodynamic parameters are outside ofthe predetermined range. In some embodiments, the method furthercomprises providing an alert if the one or more output parameters and/orthe one or more hemodynamic parameters are outside of the predeterminedrange. The inhaled NO dose may be adjusted automatically (e.g. by the NOdelivery device or a control system in communication with the NOdelivery device), or may be manually adjusted by a physician or otheruser, such as in response to an alert.

Examples of LVAD parameters that may be monitored include, but are notlimited to, pump speed (e.g. rpm), pump flow (e.g. L/min), pump power,pulsatility index, battery level, and LVAD status (e.g. operational,presence or absence of warnings).

In some embodiments, the LVAD has a minimum and/or maximum pump speedthat is set by the physician, and can be specific for the individualpatient. Alternatively or additionally, the LVAD may also have a minimumand/or maximum pump speed set by the manufacturer of the LVAD.Regardless of whether the minimum and/or maximum pump speed is set by aphysician or the manufacturer, exemplary minimum pump speeds include 100rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 6000 rpm, 700 rpm, 800 rpm, 900rpm, 1,000 rpm, 1,500 rpm, 2,000 rpm, 2,500 rpm, 3,000 rpm, 4,000 rpm,5,000 rpm, 6,000 rpm, 7,000 rpm, 8,000 rpm, 9,000 rpm, 10,000 rpm,11,000 rpm, 12,000 rpm, 13,000 rpm, 14,000 rpm and 15,000 rpm, andexemplary maximum pump speeds include 1,000 rpm, 1,500 rpm, 2,000 rpm,2,500 rpm, 3,000 rpm, 4,000 rpm, 5,000 rpm, 6,000 rpm, 7,000 rpm, 8,000rpm, 9,000 rpm, 10,000 rpm, 11,000 rpm, 12,000 rpm, 13,000 rpm, 14,000rpm, 15,000 rpm, 20,000 rpm and 30,000 rpm. The minimum and maximum pumpspeeds may depend on the design of the LVAD.

Similarly, in some embodiments, the LVAD has a minimum and/or maximumpump flow that is set by the physician, and can be specific for theindividual patient. Alternatively or additionally, the LVAD may alsohave a minimum and/or maximum pump flow set by the manufacturer of theLVAD. Regardless of whether the minimum and/or maximum pump flow is setby a physician or the manufacturer, exemplary minimum pump speedsinclude 1 L/min, 1.5 L/min, 2 L/min, 2.5 L/min, 3 L/min, 3.5 L/min, 4L/min, 4.5 L/min, 5 L/min, 6 L/min, 7 L/min, 8 L/min, 9 L/min and 10L/min, and exemplary maximum pump flows include 3 L/min, 3.5 L/min, 4L/min, 4.5 L/min, 5 L/min, 6 L/min, 7 L/min, 8 L/min, 9 L/min, 10 L/min,11 L/min, 12 L/min, 13 L/min, 14 L/min and 15 L/min. The minimum andmaximum pump flows may depend on the design of the LVAD.

In some embodiments, the pulsatility index of the LVAD has a minimumand/or maximum threshold. As explained above, the pulsatility index isthe maximum pump flow minus the minimum pump flow, divided by theaverage pump flow. As the pulsatility index is an indication of how muchsupport the LVAD is providing to the heart (a higher pulsatility indexindicates that the LVAD is providing more support), high pulsatilityindices can be a cause of concern. Accordingly, exemplary maximumpulsatility indices include values of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 20.

In some embodiments, the battery level of the LVAD is monitored. As alow battery can indicate a future or imminent shutdown of the LVAD, whenthe battery level of the LVAD drops below a certain threshold, theinhaled NO dose may be lowered, a weaning protocol may be initiated,and/or an alert is provided. Examples of minimum battery levels include30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% batteryremaining or 6 hours, 5 hours, 4 hours, 3 hours. 2 hours, 1 hour, 30minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3minutes, 2 minutes or 1 minute of battery life remaining.

Similarly, other indicators of LVAD malfunction or complete LVAD failuremay be monitored, and the inhaled NO dose may be adjusted, a weaningprotocol may be initiated and/or an alert may be provided. Again, theinhaled NO dose may be adjusted automatically (e.g. by the NO deliverydevice or a control system in communication with the NO deliverydevice), or may be manually adjusted by a physician or other user.

Another aspect of the present invention provides a method for optimizingthe inhaled NO dose for a continuous-flow or semi-pulsatile LVAD toreduce the risk of adverse events during LVAD use and/or optimizeendothelial function.

In some embodiments of this aspect, dosing would be optimized by firstoptimizing the continuous-flow LVAD settings by conventional meansand/or by the additional means described above. Next, endothelialfunction may be measured, such as by FMD and/or RHI. This adjustmentcould include the introduction of pulse modulation into the regulationof continuous-flow LVAD use and/or the use of Enhanced External CounterPulsation Therapy (EECP Therapy) to which could be used in concert withinhaled NO. Inhaled NO would be commenced at one or more doses, forvarious periods of time, following which endothelial function would bere-measured using the same technique. Inhaled NO dosing would bemodified in various stepwise fashions to identify an optimal dosingparadigm to maximize the improvement in endothelial function.Additionally, various NO-related molecules and other biomarkers ofendothelial function would be measured in blood or plasma and correlatedwith the RHI and/or FMD measurement, to provide optimal monitoring ofendothelial function to facilitate ongoing dose adjustments. Suchcorrelation may detect and/or determine the optimal parameter to measureto ensure most ideal management of dosing of inhaled NO for the purposeof optimizing and/or individualizing inhaled NO dosing to maximizeendothelial function in patients on long-term continuous-flow LVADsupport.

In some embodiments of this aspect, the inhaled NO is administered at aninitial concentration of 5 to 80 ppm. Exemplary initial inhaled NOconcentrations include about 5 ppm, about 10 ppm, about 15 ppm, about 20ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, and about 80 ppm.

As an alternative to a constant concentration of NO, the dose of NO maybe prescribed based on the patient's ideal body weight (IBW). Exemplaryinitial inhaled NO doses may be in the range of about 25 to about 150μg/kg IBW/hr, such as about 25, about 30, about 35, about 40, about 45,about 50, about 60, about 70, about 80, about 90, about 100, about 110,about 120, about 130, about 140 or about 150 μg/kg IBW/hr.

Exemplary increments for optimizing the inhaled NO dose includeadjusting the NO concentration by 0.1 ppm, 0.2 ppm, 0.5 ppm, 1 ppm, 2ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 15 ppm and20 ppm, or 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,35, 40 or 50 μg NO/kg IBW/hr.

Once the inhaled NO dose is optimized, the NO may be continued to beadministered during long-term LVAD use, such as described above.

Control System

The methods described above may be implemented in one or more devices orsystems utilizing a combination of hardware and software. It isunderstood that a control system as described herein may be a standaloneor discrete hardware and software based device which communicates withthe LVAD and the NO delivery device, or the control system may be apredominantly software-only implementation resident on the existing LVADhardware or, the control system may be a predominantly software-onlyimplementation resident on the existing NO delivery device hardware.

In various embodiments, the control system includes appropriatecomponents for transmitting and/or communicating information and/or databetween the NO delivery device, the LVAD and the control system.Communication to and from the control system may be over a communicationpath, where the communication path may be wired or wireless, and whereinsuitable hardware, firmware, and/or software may be configured tointerconnect components and/or provide electrical communications overthe communication path(s). For example, the communication path may be awireless optical line-of-sight signal (e.g. infrared signal) from onetransceiver to another transceiver or from a transmitter to a receiver.

Control System Hardware Architecture:

Regardless of the integration technique (standalone or integral to theLVAD or NO delivery device), the control system may comprise certainhardware elements as are shown in FIG. 4. Configuration 1 of FIG. 4includes an exemplary set of hardware elements for the control system.These elements can include a processing core which can be implementedusing a microprocessor, a microcontroller, a field-programmable gatearray (FPGA) or other digital logic processing device. The controlsystem can also comprise volatile and/or non-volatile memory with thevolatile memory allowing for efficient data processing, and the latterbeing resident to allow for programming of clinical scenarios oralgorithms (code) into the invention. Also resident are the processorsupport functions of clocking (oscillator) as well as a safety watchdog.Two way data communications is provided with both the LVAD and NOdelivery devices as noted earlier or simply with the other system if theinvention is implemented resident on the LVAD or NO device hardware. Abattery or wall power supply is provided to power the electronics andthis battery or wall power may be shared with the LVAD or nitric oxidedelivery devices.

Configuration 2 of FIG. 4 also provides an exemplary set of hardwareelements for the control system, which is a more expansive configurationthan Configuration 1. In Configuration 2, data is also exchanged withthe internet or cloud in order that a physician can remotely viewpatient data and remotely make adjustments to the LVAD or NO deliverydevice. It is understood that analytics specific to embodiments of theinvention and/or optimization of treatment protocols may also beprovided to the physician remotely (e.g. in the form of a cloud orinternet based application, or as a program resident on the physicianslaptop, tablet, smart phone or other device) for patient status trackingor adjustment of treatment regimens. Configuration 2 may also include auser interface for two way information exchange with the patient (orcaregiver).

If the control system is implemented integral to the NO delivery deviceor the LVAD, then many if not all of the hardware elements describedabove may already be resident on the NO delivery device or on the LVAD.

Control System Input/Output (IO) Hardware:

Regardless of whether the control system is standalone or resident onthe LVAD or NO delivery device, many of the processing tasks areunaffected and therefore may be equivalent. However, certain tasks suchas input/output routines and hardware-level code-interaction-dependenttasks (e.g. addressing of memory) may vary depending on whether thecontrol system is standalone or resident on the LVAD or NO deliverydevice.

The I/O hardware can include at least one bidirectional data port in thecase of the LVAD and NO device resident designs and at least twobidirectional data ports in the case of the standalone implementation.It is understood that this bidirectional data port is preferably anopto-isolated serial port; however, other bidirectional datacommunications schemes including parallel ports, LANs, USB, etc. arealso possible. Such bidirectional communications schemes are abundantlydescribed in the art. Further, it is possible that bidirectionalcommunications can be implemented via wireless techniques such as byoptical means such as infrared (IR) or by radio frequency (RF) meanssuch as by Bluetooth. Regardless of the communication technique, thebidirectional data transfer preferably occurs in a timely fashion.

Control System User Interface Hardware:

For a control system that is resident on the NO delivery device orresident on the LVAD, the user interface can be integrated into theexisting, yet extended, user interfaces of those devices. For instance,if the control system is implemented on a NO delivery device, thecontrol system may require additional settings, alarm and modes notcurrently resident on such a NO delivery device, and therefore the userinterface of the NO delivery device can be extended to incorporate suchinteraction. Further, in the case of a control system that is residenton an LVAD system, the LVAD system user interface can be modified toextend its functionality consistent with new modes, alarms and settings.In addition, many LVAD systems provide for data display on a device wornon the patient and also provide for clinician mediated settings on anancillary system monitor. It is understood that the functionality ofsuch ancillary system monitor user interfaces can be extended toaccommodate the control system.

Finally, in some embodiments of a control system implemented on astandalone device, the user interface can have one of at least twoconfigurations. The first configuration can include an ancillary systemmonitor which is used by the clinician to set up the system and thenremoved from the system after setup and initiation of the system. Such astrategy is consistent with the Configuration 1 of FIG. 4. Alternately,a user interface can be integrated into the control system and worn bythe user in the Balm of a module, preferably with a graphical display.Such a strategy is consistent with the more elaborate architecture ofConfiguration 2 of FIG. 4.

Control System Remote Connectivity Hardware:

As shown in FIG. 4, additional functionality may be added to the controlsystem in the form of remote connectivity capability. Hardware forimplementing such a strategy may consist of a wired or wireless link toeither a computer with an internet link or to a transceiver capable ofremote information exchange such as GSM or other remote wirelesstechniques which can be tied into an internet or cloud infrastructure.It is further understood that this remote information exchange can beimplemented using secure/encrypted data links. Other similar techniquesare known to those skilled in the art and include, for instance, currentbidirectional internet/cloud based secure data exchange schemes such asthose based on e.g, Intel's Internet of Things (IoT) architecture andsimilar emerging architectures. Remote connectivity capability caninclude a remote application programmed on a computer, a cell phone,smart phone, tablet or other device which receives information fromeither the internet or from a cloud and which displays this informationand allows for bi-directional communication with the control system formany purposes, e.g. settings adjustments.

Control System Software Architecture:

The control system can include a software component which asserts itselfas the master over the functionality of the resident NO delivery deviceand/or LVAD controllers. This software component can be responsible forcontrolling the NO delivery device and LVAD in an integrated fashionconsistent with the clinical scenarios outlined above and/or consistentwith the user-specified controller functionality specified below.

Master Slave Configuration

Regardless of whether the invention is resident on the NO deliverydevice, on the LVAD or is standalone, the control system can be capableof operating with the NO delivery device and LVAD in a master/slaveconfiguration. Specifically, the control system can assert a master rolewhen modes of operation are engaged in which the control of the LVAD andNO delivery device are controlled by the control system. This mayinclude removing the option to make settings adjustments on the LVAD orNO delivery device without overriding the master/slave configuration.Such a master/slave configuration can obviate potential controlambiguity resulting from adjustments to two or even three userinterfaces. Such a master/slave configuration can be made possible byintegrating additional code into the LVAD or NO delivery device allowingfor a master/slave configuration, or the master/slave configuration canbe implemented by allowing the control system to immediately overrideany settings changes made to the LVAD or NO delivery device. Finally,the master/slave configuration can be set and overridden by a clinicianthrough the user interface screen of the control system or remotely viaa cloud/internet based application or via a resident application on atablet, smart phone, laptop or other device.

Input/Output Parameters

The control system can utilize certain input parameters from the LVADand/or the NO delivery device, and the control system can includesoftware functionality which is implemented in such a fashion as tocommand control of aspects of the LVAD and NO delivery devicefunctionality. Further, a set of output parameters from the controlsystem can be used so that the LVAD and NO delivery device can becommanded to perform certain tasks.

An exemplary set of input and output parameters is shown in FIG. 5. Forexample, the input parameters from the NO delivery device can include,but are not limited to, the patient's respiratory rate, the current NOdelivery rate (e.g. ppm, mg/kg IBW/hr, etc.), and/or the adverse eventstatus of the NO delivery device. Exemplary input parameters from theLVAD include, but are not limited to, pump power, patient heart rate,blood flow through the pump, pulsatility index, LVAD pump speed, and/orthe adverse event status of the LVAD. Exemplary output parameters fromthe control system to the NO delivery device include, but are notlimited to, resetting/adjusting the NO delivery rate. Exemplary outputparameters from the control system to the LVAD include, but are notlimited to, resetting/adjusting the LVAD pump speed. Other relevantinput/output parameters may also be used.

As set forth above, a control system coordinating operation of the LVADand the NO delivery device may be used in any of the indications ormethods described herein. In various embodiments of this aspect, thesystem comprises a control system in communication with the NO deliverydevice and/or the LVAD, wherein the control system monitors one or moreparameters of the NO delivery device and/or one or more parameters ofthe LVAD. If one or more parameters of the NO delivery device and/orLVAD and/or of the patient are outside of a predetermined range, thecontrol system may adjust the LVAD pump settings, the inhaled NO dose,initiate a weaning protocol and/or provide an alert. The system may alsocomprise the NO delivery device and/or the LVAD itself.

In one or more embodiments, the control system reduces a pump speed ofthe LVAD if there is a failure of the NO delivery device thatdiscontinues NO administration. Failure of the NO delivery device caneither be relatively minor or may be major. The control system may alsoinitiate a weaning procedure for the NO delivery device if there is afailure of the LVAD and/or if the NO delivery device is going to beshutoff or if there is a failure of the NO delivery device. The controlsystem may also adjust the inhaled NO dose and/or provide an alert ifany of the monitored parameters are outside of the relevant range and/orif there is a failure of the LVAD and/or NO delivery device.

The control system may provide for autonomous control of LVAD and/or NOdelivery device functionality once the control systems' “rules set” hasbeen input by the clinician and once the devices have been initiated bythe clinician. The rules set may consist of initial LVAD and NO systemsettings, input vs. output parameter relationships, alarm settings,communications configuration etc. It is understood that the rules setcan be entered interactively (e.g. pump speed can be adjusted duringpatient assessment) or the rules set can be entered preemptively priorto patient use of the device(s). The rules set can be accessible througha menu-driven software program which allows the clinician to input allaspects of required system performance Some of the rules the clinicianenters may be statically set, i.e. the setting does not change once set.In some embodiments, a high pump speed alarm is an example of a staticrule. The rules may define a variable input vs. output relationship overtime; for instance, the pump speed might be commanded to be reduced overtime or further the rules set may allow the controller to controlparameter variation within predefined limits or control parametervariation through linear or non-linear control techniques in the whichinput/output parameter relationship can be controlled dynamically.

Menu-Driven Modes of Control

In one or more embodiments, the control system user interface allows forselecting a number of menu-driven control schemes in which the operationof the NO delivery device and/or LVAD is controlled consistent with theclinical needs of the patient or clinician. An example of such a mainuser interface menu is shown in FIGS. 6-8. For example, FIG. 6 shows amenu that allows for the user to select a “mode” or control scheme,which can be any of the indications or methods described above. In someembodiments, when one particular mode is enabled, the other modes aredisabled, i.e. the modes are user accessible with exclusivity. The menucan also include other user settable parameters such as alarm limits, NOdelivery device and LVAD system configuration settings for therapystartup, weaning parameters, or for the case when an active mode isdisabled (e.g. when a mode is disabled, the configuration settings wouldbe used as default settings). FIG. 7 shows an exemplary alarm settingsmenu and FIG. 8 shows an exemplary menu for setting the NO deliverydevice and/or LVAD system configuration settings. These menus caninclude submenus for setting the alarms and/or configuration settings.In some embodiments, the alarms, NO delivery device settings and/or LVADsettings may have some options disabled based on the mode selection.Further, the settings in these configuration submenus can allow fordefault settings to be locked which are returned to when none of themode selection options are active.

Exemplary modes are described in further detail below. These exemplarymodes are not intended to be limiting, and fewer than all of these modesor additional modes can be provided in a menu-driven user interface ofthe control system.

Mode 1: PH Resolution Likelihood (and Heart Transplant Viability)

The Mode 1 submenu can include settings and operational flow aimed atdetermining the patient's hemodynamic response to inhaled NOadministration for the purpose of determining if the patient mightresolve pulmonary hypertension after continued use of the LVAD. In someembodiments, this mode can also be used to assess a patient's hearttransplant viability. The mode can allow the user to input germanehemodynamic values before and/or after a NO delivery settings change.The results can be subject to clinical opinion or the results can becompared to acquired clinical study data and predictions for patientoutcome provided by the software. FIG. 9 shows one embodiment of theprogram flow for the submenu relating to this mode.

Mode 2: LVAD Setting Optimization

Mode 2 can include a method for determining the upper and lower limitsof LVAD pump speed operation concurrent with inhaled NO delivery. FIG.10 shows one embodiment of the program flow for the submenu relating tothis mode. In this mode, the pump speed (or potentially other LVADparameters) are adjusted during administration of NO in order thatcardiac output can be optimized. Specifically, an echocardiogram isutilized in this mode to determine the low pump speed settingcorresponding to the minimal pump speed necessary for the aortic valveto open with each heart beat and also to determine the high pump speedat which the septum of the heart flattens. In this mode, the user isprompted to make an initial nitric oxide setting and subsequent pumpspeed adjustments in the software. The software ultimately records thetarget pump speeds for utilization.

Mode 3: Right Ventricular Function Optimization During LVAD Use

Mode 3 can provide a method for reducing the risk of right ventricularfailure during LVAD use based on concurrent delivery of nitric oxidewith LVAD use by making settings adjustments to both the NO dose andLVAD settings. FIG. 11 shows one embodiment of the program flow for thesubmenu relating to this mode. These settings can be adjusted manually(as shown in the first portion of the flow diagram in FIG. 11) or can beadjusted by a user defined control system and user defined transferfunction and dynamic performance characteristics (see latter portion offlow diagram in FIG. 11). Monitoring of the patient can be performed byany number of clinical techniques including hemodynamic assessment.Finally, alarm limits for measured LVAD and NO delivery deviceparameters can be set.

Mode 4: Left Ventricular Functional Assessment

Mode 4 can be used to assess the status of left ventricular functionfollowing either a reduction in setting or complete cessation of theLVAD pump. FIG. 12 shows one embodiment of the program flow for thesubmenu relating to this mode. Ventricular function can be assessed bymeans of measured hemodynamic parameters such as LAP, PCWP or CO.Finally, pre- and post-pump speed adjustment hemodynamic parameterchanges may be optionally assessed by a smart algorithm (see second tolast box in FIG. 12) which provides clinical feedback based on thesehemodynamic changes about the status of the left ventricle.

Mode 5: Heart Exercise Facility

Mode 5 can be used to exercise the heart by first reducing the speed ofor stopping the LVAD pump, then preloading the left ventricle by shortterm administration of NO and then subsequently cycling off and on thedose of NO to exercise the (left ventricle) heart. An exemplary submenufor implementing this mode is shown in FIG. 13.

Mode 6: Global Control System Settings

Mode 6 can be used to set the control system, which can oversee thefunctionality of the NO delivery device and/or the LVAD. This controlsystem setting can be set to be the master control system used at alltimes during the operation of the invention or alternately it may bedisabled in particular modes previously described. The control systemsettings can provide methods for adjustment of nitric oxide dose or LVADpump speed based on the input parameters specified in FIG. 5 oralternately based on measured hemodynamic parameters input at timelyintervals by the clinician. In this mode, the clinician can be allowedto specify the input parameters and also the transfer functions betweensingle or multiple input parameters and the output parameters (e.g. pumpspeed and NO dose). The dynamic performance of this relationship canalso be user specified. Finally, timed, respiratory cycle synchronizedpulsed delivery of NO can also be specified. This may include single ormultiple pulses of NO of fixed or time-varying concentration profiles.The ability of the clinician to turn on the controller (enabling outputparameter variation in time) or to disable the controller in favor ofmaking static (output) settings adjustments can also be specified. Thesesettings can be displayed along with measured parameters and alarmsettings (as specified in another main menu item) in the main menuscreen in order that rapid assessment of patient status can be obtainedby the clinician at a glance.

LVAD

The LVAD may be any appropriate LVAD prescribed by a physician,including, but not limited to, pulsatile, semi-pulsatile (such as thosethat perform pulsatile pump speed modulation), or continuous-flow LVADs.The LVAD can have any appropriate mechanism of providing blood flow,including, but not limited to, valves, centrifugal pumps, turbines, etc.The LVAD can be internal or external to the patient. In someembodiments, the LVAD is an internal LVAD that is implanted in thepatient.

No Delivery Device

The NO delivery device may include any appropriate components foradministering inhaled NO to the patient, including flow sensors, valves,flow controllers, processors, safety shut-off valves, purge valves,tubing etc. The NO delivery device may administer a constantconcentration of inhaled NO, such as described by U.S. Pat. No.5,558,083, which is hereby incorporated by reference in its entirety. Anexample of such a NO delivery device is shown in FIG. 1. The NO deliverydevice may administer a plurality of pulses of inhaled NO to provide adose of inhaled NO that is independent of a patient's breathing pattern,such as described by U.S. Pat. No. 7,523,752, which is herebyincorporated by reference in its entirety. An example of such a NOdelivery device is shown in FIG. 2. The NO delivery device may also havethe features described in any of the following U.S. patents andpublished U.S. patent applications, which are incorporated by referencein their entireties: U.S. Pat. Nos. 8,573,209; 8,573,210; 8,770,199; andU.S. Patent App. Pub. No. 2014/0283828. Other appropriate NO deliverydevices are known in the art, such as the INOmax DSIR®, INOmax® DSand/or INOvent®.

In the exemplary NO delivery device shown in FIG. 1, a therapeuticinjector module 103 is in fluid communication with a first inlet 101 anda second inlet 102. First inlet 101 is in fluid communication withtherapeutic gas injector tube 110, which is in fluid communication witha therapeutic gas supply comprising NO. Second inlet 102 is in fluidcommunication with breathing gas delivery system 111, which isillustrated as a ventilator. The arrows in FIG. 1 indicate the directionof flow for the breathing gas and the combined gas mixture oftherapeutic gas and breathing gas. Flow sensor 106 is in fluidcommunication and downstream of second inlet 102, and monitors the flowof breathing gas through therapeutic injector module 103. The top viewof therapeutic injector module 103 is shown. The therapeutic gas andbreathing gas mix in therapeutic injector module 103 to provide a gasmixture. Injector module cable 105 connects therapeutic injector module103 with control module 109. Control module 109 comprises display 108,which can display information about NO delivery and/or any of theparameters described herein, and can provide any alerts as describedherein. Inspiratory breathing hose 112 is in fluid communication withoutlet 104 and nasal cannula 114 or other patient interface. Theinspiratory breathing hose provides the gas mixture of breathing gas andtherapeutic gas to nasal cannula 114, which delivers the gas mixture tothe patient. Patient gas sample line 113 diverts some of the flow of thegas mixture from inspiratory breathing hose 112 and brings it to sampleblock 119 for measuring NO, O₂ and/or NO₂ concentrations in the gasdelivered to the patient.

In the exemplary NO delivery device shown in FIG. 2, a supply tank 220can be in fluid communication with a tank pressure gauge 221 and aregulator 223 to bring the tank pressure down to the working pressure ofgas delivery device 222. The pharmaceutical gas can enter gas deliverydevice 222 through an inlet 224 that can provide a ready connectionbetween delivery device 222 and supply tank 220 via a conduit. Gasdelivery device 222 can have a filter 225 to ensure no contaminants caninterfere with the safe operation of the device and/or a pressure sensor227 to detect if the supply pressure is adequate and can thereafterinclude a gas shut off valve 226 as a control of the pharmaceutical gasentering deliver device 222 and to provide safety control in the eventdelivery device 222 is over delivering the pharmaceutical gas to thepatient. In the event of such over delivery, shut off valve 226 can beimmediately closed and an alarm 242 can be sounded to alert the userthat the gas delivery device has been disabled. As such, shut off valve226 can be a solenoid operated valve that can be operated from signalsdirected from a central processing unit including a microprocessor.

Downstream from shut off valve 226 can be a flow control system thatcontrols the flow of the pharmaceutical gas to the patient through thegas conduit 219 to the patient device 218 to the patient 241. Inexemplary embodiments, the flow control system can comprise a first flowcontrol valve that can be a high flow control valve 228 and a secondflow control valve that can be a low control valve 230 and there can bea first flow orifice that can be a high flow orifice 232 and a secondflow orifice that can be a low flow orifice 234. The purpose and use ofthe flow valves 228, 230 and flow orifices 232, 234 will be laterexplained. A gas flow sensor 236 can also be located in the flow ofpharmaceutical gas to patient device 218 and, as shown, can bedownstream from the flow control system, however, gas flow sensor 236may alternatively be located upstream of the flow control system.

Next, there can be a patient trigger sensor 238. When the patientbreathes in during inspiration it can create a small sub atmosphericpressure in the nose or other area where patient device 218 is located,and hence in patient device 218 itself. Patient trigger sensor 238 candetect this pressure drop and can provide a signal indicative of thestart of inspiration of the patient. Similarly, when the patientbreathes out there can be a positive pressure in patient device 218 andpatient trigger sensor 238 can detect that positive pressure and canprovide a signal indicative of the beginning of expiration. This canallow patient trigger sensor 238 to determine not only the respiratoryrate of the patient but also the inspiratory times and/or expiratorytimes. It will be understood that other techniques can be used todetermine the respiratory rate of the patient, inspiratory times, andexpiratory times, and/or other aspects of patient breathing.

There can also be a central processing unit (CPU) 240 that cancommunicate with patient trigger sensor 238, flow valves 228, 230, gasshut off valve 226, and other components in order to carry out variousexemplary embodiments of the present disclosure. CPU 240 can include aprocessing component such as a microprocessor to carry out all of thesolutions to the equations that can be used by the gas delivery device222 to deliver the predetermined quantity of the pharmaceutical gas to apatient. The CPU 420 can be connected to the front panel 210 where theuser can enter settings and monitor therapy.

As shown in FIG. 3, the NO delivery device may be in communication withthe LVAD. In the embodiment shown in FIG. 3, the control system isintegral to the NO delivery device. However, as described above, thecontrol system can also be integral to the LVAD or can be a separate,stand-alone control module.

The NO delivery device may also include components for monitoring thegas that is administered to the patient, such as gas concentrationsensors (e.g. 02, NO and/or NO₂ sensors), sampling pumps, etc. The NOdelivery device may also include redundant sensors and/or valves andhave an automatic backup delivery system in case of failure of theprimary NO delivery system. The NO delivery device may also include oneor more sensors for feedback control of the NO delivery and/or forindependent safety monitoring of NO delivery. The NO delivery device canalso provide alarms if any of the monitored parameters meet or exceed acertain level or if other safety issues are present.

The NO delivery device may be portable and light (e.g., less than 10lbs) so that it does not hinder the patient's mobility. The NO deliverydevice may run on a battery and have a battery life that meets a certainminimum criteria, such as having a battery life of at least 16 hours.The NO delivery device may also include a backup battery or other powersource.

The NO source may include two or more gas cylinders such that continuousNO administration is not interrupted when one of the gas cylinders isreplaced. Also, instead of a cylinder of NO-containing gas, the NO maybe generated bedside, such as by an appropriate chemical reaction, e.g.the reaction of a NO-releasing agent and a reductant such as ascorbicacid. Other methods for generating nitric oxide bedside are also knownin the art.

The NO delivery device may also include an automated pre-use checkoutprocedure with automatic purge to clear NO₂, and on-screen setupinstructions. The system may also have on-screen alarm help, andwireless connectivity to communicate with an electronic medical record(EMR) system or a tech support desk for remote troubleshooting. Anothersafety feature may be the incorporation of sensors and mechanisms toautomatically detect fluid or gas leaks.

The NO delivery device may have additional safety features such as aweaning protocol that slowly reduced the inhaled NO dose to avoid asudden increase in PAP. Such a weaning protocol may be initiated by a“wean button” on the NO delivery device, or may initiated automaticallyby the control system in communication with the LVAD and/or the NOdelivery device. The weaning protocol may include small changes in theNO dose, such as reducing the dose by 5 ppm for several minutes,followed by reducing the dose by a further 5 ppm for several minutes,until the patient is completely weaned off of the inhaled NO. Otherincrements for a weaning protocol include 0.1 ppm, 0.2 ppm, 0.5 ppm, 1ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 15ppm and 20 ppm, or 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40 or 50 μg/kg IBW/hr. Multiple weaning protocols may beused based on the failure detected and whether device shutoff iseminent. The weaning protocol may also be individualized for aparticular patient, such as having the weaning protocol be dependent onthe degree of the patient's current and/or prior PH.

As described above, in some embodiments the inhaled NO dose is adjustedin response to the monitoring of various parameters of the LVAD and/orthe patient. Such adjustments can include an increase or a decrease inthe inhaled NO dose (either in ppm or μg/kg IBW/hr). Increments for anadjustment include 0.1 ppm, 0.2 ppm, 0.5 ppm, 1 ppm, 2 ppm, 3 ppm, 4ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 15 ppm and 20 ppm, or0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or50 μg/kg IBW/hr.

In accordance with the invention, a method of determining whether apatient with pulmonary hypertension will resolve the pulmonaryhypertension with continued use of a left ventricular assist device(LVAD) is provided. The method may include measuring one or morepulmonary hemodynamic parameters of a patient with an LVAD to obtain afirst pulmonary hemodynamic value; after obtaining the first pulmonaryhemodynamic value, administering inhaled nitric oxide to the patientwith the LVAD; and measuring one or more pulmonary hemodynamicparameters of the patient during or after the inhaled nitric oxideadministration to obtain a second pulmonary hemodynamic value. Thedecrease in the pulmonary hemodynamic parameter from the first pulmonaryhemodynamic value to the second pulmonary hemodynamic value of at least10 mm Hg and/or at least 20% indicates that the patient is likely toresolve the pulmonary hypertension after continued use of the LVAD.

The method may further include selecting the pulmonary hemodynamicparameter from mean pulmonary artery pressure (mPAP), transpulmonarygradient (TPG) and pulmonary vascular resistance (PVR). The method mayfurther include administering the nitric oxide at a concentration of 5to 80 ppm for at least 10 minutes.

In accordance with the invention, the method may include measuring oneor more pulmonary hemodynamic parameters by performing a right heartcatheterization. The patient may be placed on a heart transplant list ifthe decrease in the pulmonary hemodynamic parameter from the firstpulmonary hemodynamic value to the second pulmonary hemodynamic value isat least 10 mm Hg and/or at least 20%. The LVAD may be explanted and adonor heart is implanted in the patient.

In accordance with the invention, a method of optimizing the settings ofa left ventricular assist device (LVAD) is provided. The method mayinclude administering inhaled nitric oxide to a patient having an LVAD;performing an echocardiogram on the patient during the administration ofinhaled nitric oxide; and adjusting or setting one or more parameters ofthe LVAD during the echocardiogram and during the administration ofinhaled nitric oxide to optimize cardiac output. The adjusting orsetting of one or more parameters of the LVAD may include one or more of(i) determining a low pump speed setting for the LVAD based on theminimal pump speed necessary for the patient's aortic valve to open witheach heart beat or (ii) determining a high speed setting for the LVADbased on the pump speed at which the septum of the patient's heartflattens. The inhaled nitric oxide may be administered at aconcentration of 5 to 80 ppm for at least 10 minutes.

In accordance with the invention, a method of reducing the risk of rightventricular failure during left ventricular assist device (LVAD) use isprovided. The method may include administering inhaled nitric oxide to apatient with an LVAD for at least 12 hours a day for at least 20 days toreduce the risk of right ventricular failure, and confirming that theLVAD is functioning before administering inhaled nitric oxide. Theinhaled nitric oxide may be administered after a patient has been weanedfrom cardiopulmonary bypass (CPB), and may be administered for at least30 days, or at least 3 months. The inhaled nitric oxide may beadministered at a concentration of 5 to 80 ppm or at a dose of 25 to 150μg/kg IBW/hr.

The method may further include monitoring one or more output parametersof the LVAD and/or one or more hemodynamic parameters of the patient,comparing the one or more output parameters and/or the one or morehemodynamic parameters to a predetermined range, adjusting the dose ofinhaled nitric oxide if the one or more outputs parameters and/or theone or more hemodynamic parameters are outside of the predeterminedrange, and providing an alert if the one or more output parametersand/or the one or more hemodynamic parameters are outside of thepredetermined range.

In accordance with the invention, a method of monitoring the leftventricle of a patient with a left ventricular assist device (LVAD) isprovided. The method may include reducing the pump speed of the LVAD orturning off the LVAD; measuring one or more pulmonary hemodynamicparameters of the patient to obtain a first pulmonary hemodynamic value;preloading the left ventricle by administering inhaled nitric oxide tothe patient; and measuring one or more pulmonary hemodynamic parametersof the patient after or during administration of inhaled nitric oxide toobtain a second pulmonary hemodynamic value. The pulmonary hemodynamicparameter may be selected from left atrial pressure (LAP), pulmonarycapillary wedge pressure (PCWP) and cardiac output (CO). The inhalednitric oxide may be administered at a concentration of 5 to 80 ppm forat least 10 minutes. Treatment may be modified by explanting the LVADfrom the patient if the left ventricle is improving. An increase in LAPand/or PCWP from the first pulmonary hemodynamic value to the secondpulmonary hemodynamic value of less than 5 mm Hg may indicate that theleft ventricle is improving.

In accordance with the invention, a method of exercising a heart of apatient having a left ventricular assist device (LVAD) is provided. Themethod may include reducing the pump speed of the LVAD or turning offthe LVAD; preloading the left ventricle by administering inhaled nitricoxide to the patient for at least 5 minutes; discontinuing the inhalednitric oxide administration; and repeating the preloading anddiscontinuation to exercise the left ventricle of the patient's heart.The preloading of the left ventricle may include administering inhalednitric oxide at a concentration of 5 to 80 ppm for a time period in therange from 5 to 30 minutes, and may be performed one to five times aday.

In accordance with the invention, a method of reducing the risk adverseevents during use of a continuous-flow or semi-pulsatile leftventricular assist device (LVAD) is provided. The method may includeadministering inhaled nitric oxide to a patient with a continuous-flowor semi-pulsatile LVAD for at least 12 hours a day for at least 20 days.The adverse events may be associated with reduced pulsatility and/orassociated with impaired NO-mediated vascular function. Beforeadministering inhaled nitric oxide, function of the LVAD may beconfirmed. The inhaled nitric oxide may be administered after a patienthas been weaned from cardiopulmonary bypass (CPB), and may beadministered for at least 30 days or 30 months. The inhaled nitric oxidemay be administered at a concentration of 5 to 80 ppm or at a dose of 25to 150 μg/kg IBW/hr.

The method may further include monitoring one or more output parametersof the LVAD and/or one or more hemodynamic parameters of the patient,comparing the one or more output parameters and/or the one or morehemodynamic parameters to a predetermined range, and adjusting the doseof inhaled nitric oxide if the one or more outputs parameters and/or theone or more hemodynamic parameters are outside of the predeterminedrange. An alert may be provided if the one or more output parametersand/or the one or more hemodynamic parameters are outside of thepredetermined range.

In accordance with the invention, a method of optimizing the dose ofinhaled nitric oxide for use with a continuous-flow or semi-pulsatileleft ventricular assist device (LVAD) is provided. The method mayinclude measuring endothelial function of a patient having acontinuous-flow or semi-pulsatile LVAD; administering inhaled nitricoxide to the patient at a first dose; measuring the endothelial functionof the patient during the administration of inhaled nitric oxide; andadjusting the dose of inhaled nitric oxide to optimize endothelialfunction. The measuring the endothelial function of the patientcomprises measuring one or more of (i) flow-mediated dilation (FMD) or(ii) reactive hyperemic index (RHI).

The method may include measuring one or NO-related molecules and/orother biomarkers of endothelial function in the patient's blood and/orplasma. The NO-related molecules may be selected from the groupconsisting of nitrite (NO₂ ⁻), nitrate (NO₃ ⁻) and nitrosohemoglobin.

In accordance with the invention, a system is provided. The system mayinclude a control system in communication with a nitric oxide deliverydevice and/or a left ventricular assist device (LVAD), wherein thecontrol system monitors one or more parameters of the nitric oxidedelivery device and/or one or more parameters of the LVAD and providesan alert if one or more parameters of the nitric oxide delivery deviceand/or the LVAD are outside of a predetermined range. The control systemmay reduce a pump speed of the LVAD if there is a failure of the nitricoxide delivery device. The control system may initiate a weaningprocedure for the nitric oxide delivery device if there is a failure ofthe LVAD. The control system may be integral to the nitric oxidedelivery device, integral to the LVAD or a component of a stand-alonecontrol module. The system may include the nitric oxide delivery deviceand the LVAD.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments” or “an embodiment” means that aparticular feature, structure, material, or characteristic described inconnection with the embodiment is included in at least one embodiment ofthe invention. Thus, the appearances of the phrases such as “in one ormore embodiments,” “in certain embodiments,” “in one embodiment” or “inan embodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, structures, materials, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

The invention claimed is:
 1. A method of optimizing the settings of aleft ventricular assist device (LVAD), the method comprising:administering inhaled nitric oxide to a patient having an LVAD;performing an echocardiogram on the patient during the administration ofinhaled nitric oxide; and adjusting or setting one or more parameters ofthe LVAD during the echocardiogram and during the administration ofinhaled nitric oxide to optimize cardiac output, wherein adjusting orsetting one or more parameters of the LVAD comprises one or more of (i)determining a low pump speed setting for the LVAD based on the minimalpump speed necessary for the patient's aortic valve to open with eachheart beat or (ii) determining a high speed setting for the LVAD basedon the pump speed at which the septum of the patient's heart flattens.2. The method of claim 1, wherein the inhaled nitric oxide isadministered at a concentration of 5 to 80 ppm for at least 10 minutes.3. A method of monitoring the left ventricle of a patient with a leftventricular assist device (LVAD), the method comprising: reducing thepump speed of the LVAD or turning off the LVAD; measuring one or morepulmonary hemodynamic parameters of the patient to obtain a firstpulmonary hemodynamic value; preloading the left ventricle byadministering inhaled nitric oxide to the patient; and measuring one ormore pulmonary hemodynamic parameters of the patient after or duringadministration of inhaled nitric oxide to obtain a second pulmonaryhemodynamic value, wherein an increase in LAP and/or PCWP from the firstpulmonary hemodynamic value to the second pulmonary hemodynamic value ofless than 5 mm Hg indicates that the left ventricle is improving.
 4. Themethod of claim 3, wherein the pulmonary hemodynamic parameter isselected from left atrial pressure (LAP), pulmonary capillary wedgepressure (PCWP) and cardiac output (CO).
 5. The method of claim 3,wherein the inhaled nitric oxide is administered at a concentration of 5to 80 ppm for at least 10 minutes.
 6. The method of claim 3, furthercomprising modifying treatment if the left ventricle is improving, themodifying comprising explanting the LVAD from the patient.
 7. The methodof claim 3, wherein preloading the left ventricle comprisesadministering inhaled nitric oxide at a concentration of 5 to 80 ppm fora time period in the range from 5 to 30 minutes, said preloading beingperformed between one and five times per day.
 8. The method of claim 3,further comprising exercising the heart, the exercising comprising:discontinuing the inhaled nitric oxide administration; and repeating thepreloading and discontinuation to exercise the left ventricle of thepatient's heart.